\r\n\tTopics covered include but are not limited to: Hydrologic Cycle (Precipitation, Runoff, Infiltration and their Measurement, Land surface interaction); Hydrologic Analysis (Hydrograph, Wave routing, Hydrologic statistics, Frequency Analysis); Applied Hydrology (Applications in Engineering, Sciences and Agriculture, Design storms, Risk analysis, Case studies); Computational Hydrology (Numerical modeling, Hydrologic modeling and forecasting, Flow visualization, Model validation, Parameter estimation); Interdisciplinary Hydrology (Hydrometeorology, Impact of Climate Change, Precipitation data analysis, Mathematical concepts, Natural hazards); Radar Hydrology (Precipitation estimation techniques, Promise and Challenges in Radar technology, Uncertainty in radar precipitation estimates).
\r\n
\r\n\tThe contents covered in this book will serve as a valuable reference guide to students, researchers, government agencies and practicing engineers who work in hydrology and related areas. We hope that this book will open new directions in basic and applied research in hydrological science.
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1. Introduction
1.1 Epidemic disease
The term epidemic is derived from Greek word “epi” meaning “upon” and “demos” meaning “people”. It refers to a communicable disease which spreads rapidly in a given population within a very short period of time. Any infectious disease existing in a region does not make it epidemic unless it causes faster mortality. A death rate of around 1.6 folds higher than usual death rate (baseline) caused by a disease in a population within a fixed period could be considered as an epidemic disease. A disease lower than this fold increase, observed in a population could be designated as an outbreak of a disease [1].
Diseases like tuberculosis, hepatitis, yellow fever, chikungunya, ebola virus disease, marburg virus disease, Crimean-Congo haemorrhagic fever, rift valley fever, typhoid fever, Shigellosis, plague, lassa fever, West Nile fever, zika virus disease, meningitis, MERS-CoV, plague, monkeypox, nodding syndrome, nipah virus infection are considered as epidemic diseases as per World Health Organization [2]. Epidemic diseases like plague, small pox and cholera caused unsurpassed deaths in human population till the end of eighteenth century [3].
1.2 Pandemic disease
The term pandemic is derived from Greek word “pan” meaning “all” and “demos” meaning “people”. It refers to an epidemic disease which spreads among large population possibly across geographic locations or continents within a short time span [4].
Influenza, along with viral pneumonia, HIV and cholera are considered as pandemic disease and caused millions to die beside high rate of hospitalization and life threatening conditions across the globe [2]. The viral diseases like Influenza, cholera and HIV caused maximum deaths in the twenty-first century [3].
1.3 Vaccination
Vaccines are available for most of the epidemic and pandemic diseases [5]. Vaccination is the most effective prevention technique to suppress the infection in healthy population [6]. However, poor and conflicted regions of Asia and Africa are deprived of these vaccines [7]. World Health Organization plays a major role in epidemic preparedness in these regions and provides extended healthcare facilities during an epidemic outbreak [8].
1.4 Global requirement
Considering, the disease outbreak and its transmission is high in a poor population of developing region [9]. First line and second line antibiotics are the most effective medicines for infected subjects as the vaccines are ineffective after the infection had taken place. First line therapy includes antibiotics are the most commonly prescribed medicines to alleviate the infection process, often not responsive on several types of multi drug resistant infection [10]. Hence it is important to select a cost effective model to screen the first line antibiotics or antivirals.
1.5 Fruit fly as a model organism for drug screening
Today, we need to discover more efficacious antibiotics to fight the infectious diseases. Drosophila melanogaster could be a useful model organism to study the infection process and to screen an efficient drug. Due to its shorter lifespan and vast genetic similarity towards vertebrates allows conducting the drug screening experiments. It is reviewed here that Drosophila melanogaster was already been used to study infections caused by pandemic and epidemic diseases. But how to utilize the fruit flies to study different infectious disease and techniques to screen a potential drug candidate were not well reviewed.
As per World Health Organization lower respiratory tract infections are caused mainly by influenza, pneumococcal pneumonia and viral pneumonia are responsible for 3 million deaths [11]. The WHO reported in 2018, 3–5 million cases of Influenza with 290,000–650,000 death cases annually [12]. As per the Global Disease burden (GDB) study report of 2015 there were around 1.5 million deaths in all age groups caused due to pneumococcal pneumonia [13]. SARS (Corona virus) causes viral pneumonia; it is epidemic to more than 30 countries with 8000 reported cases and 774 deaths during the year 2002–2003. MERS is a viral pneumonia causing infections in 688 persons and 282 deaths reported by WHO in 20 countries during 2012 [14].
2.2 Influenza
Influenza originates from Orthomyxoviridae family it can be differentiated into three types Influenza pandemic caused by Influenza A/B virus, seasonal Influenza and avian influenza (H5N1) [15]. Influenza virus causes upper respiratory tract infection often found to cause lower respiratory tract infection in association with bacterial co-invasion. The seasonal influenza leads to maximum hospitalization resulting fatality in infants during the seasonal outbreak [16].
2.3 Pneumonia and viral pneumonia
Pneumonia is caused due to several communicable infections usually known as community acquired pneumonia (CAP), often seen in hospitalized patients. Pneumonia can be caused by bacteria like Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Chlamydia pneumoniae, Staphylococcus aureus, Klebsiella pneumonia and Mycoplasma pneumonia. Viruses like syncytial virus, adenovirus, rhinovirus, metapneumovirus, Influenza A/B viruses, Coronaviruses, parainfluenza virus including MERS and SARS causes viral pneumonia [17]. The viral pneumonia is the influenza often associated with bacterial infection thereby causing fatality better known as superinfection [18].
2.4 Tuberculosis
Tuberculosis is caused by Mycobacterium tuberculosis, a gram negative facultative anaerobic bacteria. In 2017 around 10 million people were infected with tuberculosis causing mycobacterium killing 1.6 million peoples across the world [19]. The current estimate of tuberculosis is not significantly different from the 2015 WHO report [20].
2.5 HIV
Currently HIV is the most fatal disease observed in human population across the globe. It caused maximum number of deaths around the world in the last 3 decades. As per the latest WHO report of 2019, HIV/AIDS have claimed more than 35 million deaths till date. Currently 36.9 million (31.1–43.9 million) peoples are living with HIV as of 2017 [21]. Although the rate of infection has decreased in the recent years, still HIV remains a global burden on world economy.
2.6 Diarrhoeal disease
2.6.1 Cholera
The term “cholera” was derived from Sanskrit meaning “stomach disturbance” [22]. Since, early 1800 century cholera outbreak turned out to be pandemic and caused millions to die, altogether six different pandemics took place the seventh started in the year 1961 and is still ongoing [23, 24]. In 2019 WHO report suggests 1.3 million to 4.0 million cases of cholera with an estimated 21,000–143,000 deaths worldwide [25].
2.7 Hepatitis
Viral hepatitis is one of the most life threatening disease, it causes death to 1.4 million peoples across the globe reported in 2018 [26]. Globally around 260 million peoples are infected with HBV and 71 million with HCV infections are reported causing 90% of deaths among viral hepatitis patients [27]. The HBV and HCV has the highest prevalence rate in the global population at present, hepatitis viruses like HAV, HAD and HEV are endemic in many countries [26]. Currently there is no vaccine available for HCV till date.
2.8 Typhoid
The term Typhoid was coined from the Greek word “typhus” which means “Smoky” was used to relate the delirium symptom often associated with typhoid fever [28]. Typhoid fever is caused by gram-negative bacteria known as Salmonella enterica serovar typhi. Around 11–21 million cases of typhoid fever outbreak are reported annually, among that it causes death of 128,000–161,000 individuals worldwide [29].
2.9 Malaria
Malaria fever is a severe parasitic disease caused by Plasmodium falciparum and Plasmodium vivax transmits through female Anopheles gambiae mosquitoes. In the year 2017 219 million cases were noted by World Health Organization, this seasonal outbreak of malaria in 87 countries led to 435,000 deaths [30].
2.10 Viral meningitis, viral encephalitis and hemorrhagic fever viruses
Viruses like herpes simplex virus HSV, HIV, mumps virus, measles virus and west Nile virus causes meningitis which causes frequent outbreaks in some regions [31]. Japanese encephalitis virus along with genus Alphavirus Togaviridae family viruses are arbovirus (arthropod borne virus) like California encephalitis, Chikungunya, dengue, Eastern equine encephalitis, Powassan, St. Louis encephalitis, Sindbis virus, West Nile, Yellow Fever and Zika virus are capable of causing encephalitis in humans [32, 33]. The viruses capable of causing hemorrhagic fever are dengue virus, rift valley virus, yellow virus, Crimean-Congo Hemorrhagic Fever, Lassa virus, Marburg virus and Ebola virus are epidemic diseases [34].
3. Drosophila model to study highly infectious diseases
There are at present several bacterial, fungal and viral models of infection which were successfully demonstrated to infect flies and used it to understand drug efficacy. Drosophila model of infectious disease could be very low cost model to study drug efficacy in-vivo; it could help to save lives by saving time during an epidemic outbreak. Understanding the disease pathogenesis in humans and drawing out a similar model in Drosophila melanogaster would suggest the target genes and proteins responsible for the underlying disease [35].
In the recent past several research works has been conducted to understand the immune system of Drosophila melanogaster. At present the immune system of Drosophila is a well-studied model to study infectious disease [35]. Adult flies have brain, heart, lung (spiracle), liver (fat body), kidney (renal tubule), GI tract (gut/crop), ovary/testis and versatile circulatory system (hemocyte) [36]. Apart from physiological resemblance Drosophila has 75% genetical similarity with human disease genes, due to this fact genetically tractable model could be generated to what extent is discussed here [35].
4. Host-pathogen interaction
Drosophila melanogaster has a well-built immune system to withstand pathogenic incursion, comprising of cellular, humoral and innate immunity in an effective but in simpler form than humans [37]. However, due to evolutionarily conserved immune pathways found in vertebrates and invertebrates, several components of fly immune system are homologous to humans [38]. The immune activation in flies against pathogens involves processes like recognition, coagulation, melanisation, phagocytosis, apoptosis, regulation of iron metabolism, synthesis of antimicrobial peptides and production of reactive oxygen species [39].
The bacterial and fungal infection leads to the activation of dToll, Imd, Eiger (TNF family homolog) and insulin like receptors (FOXO) in Drosophila. The drosophila toll and Imd (immune deficiency) pathways function as innate immunity. Toll receptors in flies play an important part during viral, fungal and bacterial infection. The patterns recognition receptors (PRRs) initiate the signal in fly immune system depending on the type of pathogen upon interaction [40]. Gram positive and gram negative bacterial infection activates peptidoglycan recognition protein SA (PGRP-SA) and Gram-negative binding protein 1 (GNBP1) respectively. PGRP-SA causes proteolytic cleavage of Spatzle upon stimulation of dToll, it mediates downstream signalling of dMyD88, Tube, Pelle, and DIF (dorsalrelated immunity factor) the NF-kB homolog. Imd an intracellular signalling protein located close to the transmembrane PGRP-LE and PGRP-LC proteins, activates Relish protein to trigger autophagy and phagocytosis through ImD regulated genes by rendering cellular immunity against gram negative bacteria [41]. Toll activates the nuclear factor DIF and it promotes humoral immunity in the fat body by producing varieties of anti-microbial peptides AMPs like attacin, cecropin, drosomycin, defensin, metchnikowin, diptericin and drosocin [42].
The fungal pathogen was found to be recognized by GNBP3 along with PGRPSA and GNBP1 it activates the drosophila toll receptors [43]. The Drosophila toll-5 (Tehao) and toll-9 plays major role during fungal infection by inducing Drosomycin gene [44].
During the preliminary stage of viral infection Drosophila toll receptor homolog of human TLR, Imd (TNF-alpha), Domeless (Jak–STAT), and RNAi plays a major role against viral infection these are components of innate immune system [45]. Similar to humans the viral glycoproteins are recognized by toll receptors like toll-4, while toll-7 dependent autophagy observed during viral infection in flies [42, 46]. Jak–STAT and Imd together mediates effective immunity against viral attack in flies [47]. The domeless-hop-stat2 pathway stimulated by upd1/2/3 activates Jak–STAT regulated genes responsible for controlling viral load; it is homologous to mammalian Jak–STAT pathway [48]. The Drosophila P53 and dP38 mediates apoptosis in flies upon stress response generated due to DNA damage, P53 mediated apoptotic genes are regulated by Jak–STAT-MAPK [49]. The dP38 stimulation in flies triggers Unpraired gene (upd protein) a mammalian IL-6 homolog further activates Jak–STAT-Turandots pathway which increases tolerance towards the viral invasion [50]. The intrinsic to cell the Dicer2 a viral sensor protein mediates silencing through RNA-induced silencing complex (RISC) dependent RNAi production which inhibits viral components transcription and vago gene activation finally controls viral growth [51, 52]. The anti-viral RNAi are transported from one cell to another through canonical nano-tubes structures [53]. dERK pathway regulates viral infection of flies gut epithelial infection during orally challenge of arbovirus, Sindbis virus and vesicular stomatitis virus [54]. Despite of dynamic immune response against the viral infection viruses like Nora virus, Sigma virus (DmelSV), Drosophila C virus (DCV), and Drosophila X virus (DXV) can cause fatality in flies [55].
5. Markers of infectious diseases
In the recent decades extensive research has been conducted to understand the regulation of immune system in Drosophila melanogaster. Using techniques like genome wide screens, Drosophila S2 cell line in-vitro models and tissue specific loss of function mutation in transgenic GAL4/UAS fly allows studying selective pathways of immune response [56]. Up-regulation of antimicrobial peptides (AMP) in flies during bacterial and fungal infection was frequently observed, these six AMP genes expression level could be analyzed in flies [42, 57]. ROS level in flies trigger several pathways responsible for tolerance (cell survival) and apoptosis (cell death) could be assayed in virally infected flies [49, 50]. Rescue of diseased transgenic flies upon feeding of desired drug could reveal drug efficacy [56]. Survival of flies would further reveal the effect of drugs during an ongoing pathogenesis [58].
6. Behavioral and physiological characterization of infected flies
6.1 Negative geotaxis assay
Negative geotaxis assay serves the purpose to manifest ongoing pathogenesis inside the live model. It was demonstrated previously that infected flies display significantly lesser motility than healthy flies when exposed under bright light. It could be considered as an important parameter to explain drug efficacy while screening anti-microbial drugs in flies [59].
6.2 Circadian rhythm
Circadian rhythm in flies was studied, the genes timeless or period controls the circadian rhythm of activity-sleep cycle during day-night respectively. It has been observed that infected flies exhibit interrupted circadian control of locomotion thus flies with this deficit shows restlessness at the same time gets lesser sleep than normal flies. The behavioral changes could also be studied in infected flies beside the control/uninfected flies [60].
6.3 Wasting
Wasting is commonly seen physiological changes associated with prolonged diseased condition in humans. Wasting is a common symptom in HIV/AIDS, tuberculosis and cholera patients. Similarly rapid loss in weight could be seen in infected flies prior to its death [61, 62].
7. Factors contributing to suitable infection model
It was previously reported that in order to replicate the outcome of future studies it is important to optimize the lethal dosage selection and the route of inoculum [63]. It is suggested that the selection of microbial strain and gender of flies are two important factors which could potentially impact the findings of future research.
7.1 Route of inoculum
There are two prime techniques for inducing infection in flies, primarily by feeding the flies with the microbes secondly by pricking micro needles dipped in bacterial liquid (inoculum) into fly’s abdomen or thorax [62, 63]. Flies could be pricked in the abdomen with micro-needle dipped in the microbial solution, known amount can be useful in pharmacodynamic as well as pharmacokinetic studies [64].
7.2 Flies gender selection
Selecting gender should be considered strictly, few studies do not prefer to report the reason behind choosing the gender male/female type. In a study with Vibrio cholera infection narrated that female flies survived approximately 24 h longer than male flies [65].
8. In-vivo models for epidemic and pandemic diseases
The existing models using live bacterial infusion, feeding fungal strains and transgenic flies expressing viral proteins. Under immuno-suppressed condition would serve multiple purposes like studying host pathogen interaction and conducting preclinical trials [62, 66].
8.1 HIV models
Since human viruses do not usually invade insects the use of Drosophila melanogaster as a model organism is critical and currently in less usage [67]. In order to establish an HIV model for drug screening in Drosophila melanogaster it is important to understand the structural components of human immunodeficiency virus (HIV). The envelope components are comprised of Gp120 and Gp41 encoded by env sequence, pol-Gag RNA material encodes for Matrix, capcid, nuclear capsid, p6, Protease, reverse transcriptase, and Integrase), Vif, Vpr, Nef, vpu, tat, and Rev [68]. Transfection of Tat (transcription activator), Vpu (helps virion budding), Nef (regulator of structural gene expression) and Rev. (Nuclear export protein) in flies (in-vitro/in-vivo) were previously shown, these transfection models could be useful due to the fact that there is no marketed drug to target these viral proteins [69].
The incapacity of Drosophila S2 cells is only associated with the expression of HIV-1 envelope proteins. It is possible to express gycosylated and cleaved Gp120 in S2 cells but fusion with CD4+ receptors of T-helper cells could not be achieved in the model expression system [70]. In another study the expression of Gp120 in drosophila was carried out in S2 cell line, the antigen Gp-120 did not exhibited T-helper cell mediated humoral immune system activation and IgG antibody generation, when introduced in mice [71]. Due to this usual challenge in a different study they expressed HIV-1 virus like proteins in Drosophila S2 cells [72].
The nef transgenic flies exhibited JNK mediated apoptosis further nef inhibits NF-kB necessary for Relish gene activation similarly decreased immune response is common in AIDS patients [73]. In a study transfected viral protein Vpu was shown to cause immune suppression in fat body of flies via toll dependent pathway, in wings the Vpu expression caused apoptosis and hindered wing development, in mammals Vpu is known for causing T-cell lymphocyte death in infected patients [74, 75]. Active microbial invasion in nef flies should be further confirmed before targeting with potent anti-nef drug candidate. The Rev transfected S2 cells revealed that expression of Rev. protein directed the translocation of viral mRNA sequence into the cytoplasm, blocked by leptomycin B a secondary metabolite of Streptomyces species [76]. Leptomycin B remained unapproved in clinical trials due to high toxicity in cancer patients [77]. The ART drugs like zidovudine, lamivudine, stavudine, didanosine and abacavir were introduced in D. melanogaster to study genotoxicity profile [78, 79]. In Drosophila oocytes Tat a nuclear shuttling protein, displayed interaction with tubulin causing dorso-ventral axis mislocalization resulting in delayed microtubule polymerization, similarly tubulin dysfunction causes neurological symptoms observed in HIV+ individuals [80]. The transfected viral proteins in live Drosophila could be used to target drug in a thoughtfully designed model.
Cryptococcosis, Candidiasis and Aspergillosis are common types of fungal infections observed as clinical challenge in HIV-positive patients [81]. Under immunosuppressed condition the invasion of fungi in flies causes fatality. In Drosophila fungal infection could be difficult to achieve as the innate immune system mediates anti-fungal peptide production by haemocyte causing decrease of fungal load and increases fly survival rate [82]. Hence Toll mutant flies were generated and used to induce fungal infection.
Fluconazole and voriconazole showed anti-fungal activity against Candida albicans and Aspergilus fumigatus respectively in flies [64, 83]. Among Cryptococcus species only Cryptococcus neoformans is capable of killing flies with mutated toll receptors in drosophila, susceptible to infection acquired from Cryptococcus species like Cryptococcus kuetzingii or Cryptococcus laurentii [83]. Although, the toll mutant flies do not demonstrate an HIV model, it is used to induce fungal infection which can serve as a model for fungal infection in Drosophila for drug screening purpose.
In order to study HPV and EBV there are two model systems to study the effect in flies. In the study with HPV co-expression of viral oncoprotein E6 and human UBE3A did not resulted in tumorigenesis requires Ras or Notch pathway in flies, E6-UBE3A requires insulin receptors for cancer to develop [84]. Upon introducing the BZLF1 gene of EBV led to interaction with shaven gene in flies a homolog of pax gene family of humans responsible for B-cell development [85]. Expression of BRLF1 and BZLF1 genes using GMR-R model in Drosophila showed BRLF1 caused overproliferation of cells in flies whereas, BZLF1 resulted in interaction with several tumor suppressor genes and both viral genes showed interactions with core tumor suppressor genes like reaper, p53, Rab5, and Tor [86]. EVB DNA injection in flies caused Imd mediated pathway to increase diptericin production at the same time hemocyte proliferation and remarkable increase in numbers of hemocyte cells [87]. Human cytomegalovirus derived immediate early gene transfection in flies resulted in embryonic lethality similar to humans [88].
8.2 Influenza infection models
Influenza virus like most other viruses fails to infect the Drosophila melanogaster. To construct a suitable model for drug screening was also an important aspect due to high mortality rate caused by flu virus. The influenza virus coat protein consists of hemagglutinin (HA) and neuraminidase (NA). Matrix protein 2 (M2) plays a vital role in maintaining the pH level through proton transport enabling viral uncoating. Expression of M2 protein in flies is achieved through insertion of M2 cDNA sequence in upstream activation sequence (UAS) of pCaSpeR3 p-element insertion vector gave rise to UAS-M2 flies. The crossover between UAS-M2 and C135-Gal4 flies resulted in death at the pupal stage. Therefore the larvae were exposed and not the adult flies to anti-influenza drug amantidine which is a M2 antagonist. Amantadine and several other drugs of its class are not capable of acting against the flu virus due to varying viral strain types. Moving further the flu-fly model of UAS-M2 could be used to study potential anti-influenza drug [56].
8.3 Pneumococcal pneumonia models
There are several pneumococcal pneumonia infection model studied in drosophila using Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumonia. The biofilm formation is widely observed during Streptococcus pneumoniae infection in humans [89]. The nasopharyngeal tract is colonized primarily by these gram positive rods bacteria prior to infecting the lower respiratory tract. Similarly the Pseudomonas aeruginosa exhibit the biofilm formation during nasocomial infection in humans, a common culprit causing community acquired pneumonia hospitalized in patients [57, 90]. Pseudomonas aeruginosa was shown to infect Drosophila melanogaster causing its gut epithelium inflammation [57].
Staphylococcus aureus causes osteomyelitis, endocarditis, septicaemia and pneumoniae in humans, it can be selected for mimicking pneumoniae infection in Drosophila [91]. Staphylococcus aureus caused rapid death of flies within 48 h due to inoculation of high lethal dosage, extended survival seen upon exposure to antibiotic (tetracycline) [92]. The teichoic acid of peptidoglycan layer in Staphylococcus aureus was found to suppress the toll receptors of flies similar to Streptococcus pneumoniae toxins autolysin and pneumolysin interacts with toll receptors of macrophages in human [93, 94, 95]. Klebsiella pneumonia the gram positive bacteria are capable of killing drosophila at higher dose [96]. Streptococcus pneumoniae causes the maximum deaths in human causing pneumoniae which could be used as a suitable model for antibiotic screening in Drosophila melanogaster.
8.4 Tuberculosis models
There are at present two bacterial models for studying mycobacterium infection in flies, induced by Mycobacterium marinum and Mycobacterium abscessus. Mycobacterium marinum is a non spore forming, non motile, gram positive acid-fast bacillus, which is genetically 99.3% similar to Mycobacterium tuberculosis [97, 98]. Vacuole acidification is inhibited by M. marinum in drosophila phagocytic cells has been previously identified to be similar with tuberculosis pathogenesis in humans [99, 100]. Tigecycline plus linezolid was shown to have extended fly survival during the Mycobacterium abscessus infection. Rifampicin a very potential wide range antibiotics effective to inhibit multi drug resistance tuberculosis (MDRTb), it showed antimycobacterial efficacy in Drosophila infected with Mycobacterium marinum [101]. Any potential drug candidate capable of anti-mycobacterial activity can be studied in these models.
8.5 Cholera models
The bacteria Vibrio cholerae is a gram-negative and motile bacterium causes diarrheal disease in human. The pathogenesis of Vibrio cholera infection in humans was previously reported to be symbolized as comparable disease progression in Drosophila melanogaster. Ingestion of cholera bacterium results in lethal infection induced by the toxins in the intestinal cells of the flies. The toxins ingestion could not cause equivalent lethal effect on flies was explained previously. The V. cholera infection results in inhibition of adenylyl cyclase, Gsα, or the Gardos K+ channel causing death due to oral ingestion in flies. Clotrimazole a Potassium Calcium-Activated Channel Subfamily N Member 4 (KCNN4) inhibitor exposure increased flies susceptibility to V. cholera infection [61]. Quorum sensing is the ability to detect and to respond to a specific density of cell population through gene regulation [102]. Drosophila melanogaster initiates quorum sensing during vibrio cholera infection by suppressing succinate (substrate of KEBS cycle) uptake in flies intestine, limiting the wasting process [62]. Quorum sensing enables the bacterium to remain sessile in the flies gut and Vibrio polysaccharide (VPS) gene expression was shown to have increased during V. cholera infection of flies [103].
9. Importance of in-vitro model infection in Drosophila
The Drosophila S2 cells were first discovered by I. Schneider in 1972 [104]. S2 cells are derived from primary cell culture of late phase embryo of Drosophila melanogaster. S2 cells are macrophage like cells potentially grows in serum free medium as non-adherent suspension. S2 cells can express variety of heterologous proteins, upto 12 proteins could be co-expressed at a time in highly controlled manner, doubling at a rate equivalent to any cell lines derived from human cancerous cell line [105]. These cells do not form coherent clusters with no noisy gene expression profiles by maintaining uniformity during expression and chromosomal aneuploidy gets compensated during expression self adjusted to one gene copy number per cell unlike cancerous lineage [106]. These viable and potent cellular characteristics of S2 cell allows to be chosen for vaccine development, large scale enzyme as well as hormones production similar to Chinese hamster ovary CHO cell lines [104, 107]. The post translational glycosylation process is often not achievable in S2 cells making it disadvantageous [105]. The viral infections models are slow in inducing fatality in immuno-suppressed mutant flies, 50% death occurs after around 18–30 days post infection in live model [44, 108]. Therefore, S2 cell line model could requite certain challenges usually observed during in-vivo infection models.
10. In-vitro model of epidemic and pandemic infectious disease
Using drosophila S2 cell model a study showed that intercellular Mycobacterium smegmatis growth inside the host phagosomes is restricted by Rab7, CG8743, and the ESCRT factors [109]. Cryptococcus neoformans a fungi responsible for meningoencephalitis infection, S2 cells infected by this fungus up-regulates autophagy initiating proteins like Atg2a, Atg5 and Atg9a beside lysosomal markers like LAMP-1 and cathepsin D [110]. The hepatitis B virus surface antigen (HBsAg) coded by S gene was transfected in S2 cell line gave rise to no variation in expressed protein suggesting S2 cells useful for expression system [111]. The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) was expressed in S2 cells of Drosophila to produce non-glycosylated variants capable of binding to its receptor in rabbits resulted in IgG production against PfRH5 protein [112]. Highly potential vaccine VAR2CSA against malaria was successfully produced in S2 cells of Drosophila melanogaster [113].
11. Viral meningitis, encephalitis and hemorrhagic fever S2 cell line model
Herpes simplex virus was studied in Drosophila S2 cells where transfection of two viral proteins PILRα and gB responsible for binding to mammalian cells were expressed found to be poorly glycosylated [114]. The RNAi pathway was indulged by host cells to inhibit the Dengue virus (Flavivirus family) infection, by knocking down Argonaute (Ago1/2) and Dicer (Dcr1/2) showed sustained viral infection, currently clinical trial is underway NCT00936429 [115, 116]. Japanese encephalitis virus envelope glycoprotein E transfected in Drosophila S2 cells resulted in stable protein expression, this glycoprotein exposure in mice led antibody production against it [117]. Infection of Sindbis virus in live flies led activation of Notch, Jak–STAT and ImD pathway to intervene viral invasion [54]. Notch pathway mediated assimilation of ankyrin, plap, syx13, unc-13, csp, rab1 and rab8 during Sindbis virus infection in S2 cells [115]. The human antibody MR191 specific against Marburg virus was fused with recombinant RAVV GP ectodomain produced in S2 cell line [118]. The Zika virus structural envelope (E) protein were efficiently produced and secreted from transfected Drosophila S2 cell line model [119]. Flies produces RNAi against west Nile virus infection as a result of innate immune response similarly it was seen in S2 cell line, S2 cell lines were used for WNV infection, currently vaccine development NCT01477580 and NCT00707642 is underway [116, 120]. In a study mice were injected with glycoprotein GP of Ebola virus expressed in Drosophila S2 cell line found to produce antibodies against the infused antigen [121] (Table 1).
Epidemic/Pandemic Disease
Microbes
Vaccine/Drugs screened or derived out of fly model (in-vitro/in-vivo)
References
HIV/AIDS
Human Immuno virus
Leptomycin B (In-Vitro) Unapproved under clinical trials Zidovudine, lamivudine, stavudine, didanosine, Abacavir
List of Drugs/vaccines screened or developed against Infectious diseases in Drosophila melanogaster as a model organism.
12. Disadvantages of Drosophila model for drug screening
Drosophila melanogaster being ectothermic organism unlike humans are endothermic homeotherms maintains physiological temperature constantly at 37°C, making it difficult to infect flies with bacteria like Mycobacterium tuberculosis grows strictly at 37°C [36, 122]. Several pathogenic viruses capable of infecting humans cannot naturally infect Drosophila melanogaster [55, 67]. The fungal dose response in flies is difficult to measure in oral infection model therefore this model is limited to study only the anti-fungal drug efficacy [64]. The presence of symbiotic microbes like Wolbachia a gram negative bacteria associate mostly with drosophila gut, improves the fly immunity against viral infection [123]. Superinfection like viral pneumonia cannot be studied at present to undertake preclinical trial using fly as a model.
13. Future perspective
Irrespective of multiple disadvantages flies could be used for studying drug efficacy. Multi-drug resistance tuberculosis infection could be studied in flies. The ART medication impairs human heart by causing prolonged QT, prolonged arrhythmic condition leads to myocardial infraction, Drosophila could be a suitable model to study the effect of anti retroviral therapy on fly heart [124, 125, 126]. Shockingly infection induced in flies by vesicular stomatitis virus in toll-7 depleted flies where 50% flies displayed death after 18 days, suggesting HIV infection could also kill toll7 mutant flies, as toll mutant flies displayed fungal invasion, this yet to be confirmed [44]. Alternative to this only viral DNA had been shown in a recent study to evoke immune activation in Drosophila by injecting it in thoracic region [87]. Kaposi sarcoma associated Herpesvirus (KSHV) needs a model which is yet to be studied in flies, however the KSHV viral gene latent nuclear antigen (LANA) interacts with RING3 of human which is homologous to drosophila female sterile homeotic (fsh) has already been identified [127]. Drosophila wound healing an important concern while inducing bacterial infection currently it is well understood and was found regulated by EGFR/ERK pathway essential for tissue repair [128]. The RNAi screens against Dengue or Influenza virus infection in cell culture could not identify Jak–STAT, ImD and toll dependent gene activation suggesting possible alternative pathway associated in infection modulation and no stimulation of inflammatory cytokine activation [40]. The food borne Salmonella typhimurium causes stomach flu (gastroenteritis) is well studied in Drosophila, but not epidemic pathogen Salmonella typhi.
14. Conclusions
Currently the existing models of infection in drosophila are capable of causing infection using viruses, bacteria (gram negative and gram positive) and fungi. These models are of great use since the efficacy of a drug capable of modifying diseased condition could be studied in detail in live Drosophila or in-vitro S2 cell. In this detailed review on epidemiology of infectious disease, it could be predicted that infection alone is a threat to overall population imposing death to more than 5 million individuals. Diseases like influenza, HIV, pneumonia, tuberculosis and cholera could be studied in flies. Currently there are 20 diseases which caused epidemic worldwide [2], 13 of the pathogens were studied in Drosophila melanogaster and diseases caused by yellow fever virus, Nipah virus, MERS, Hepatitis C virus, Salmonella typhi, Crimean congo hemorrhagic fever virus, chikungunya virus, monkeypox virus, Nipah virus and shigellosis bacteria are yet to be studied in-vitro/in-vivo. These diseases are of pandemic and epidemic criteria it causes huge number of deaths globally. Controlling the epidemic and pandemic diseases should be the main focus of the healthcare sector in the next decade.
Acknowledgments
I would like to thank Professor Sarat Chandra Yenisetti, Nagaland University, India for the effort and advices given for this article. I would like to thank Professor David S. Schneider of Stanford University, USA for clearing doubts regarding tuberculosis and typhoid infection in flies.
Conflict of interest
The author has no conflict of interest.
Notes/Thanks/Other declarations
I would like to thank the IntechOpen Journal for giving 100% waiver to publish this review article. I would like to thank all the researchers for providing their complete articles which are unavailable online.
\n',keywords:"Drosophila melanogaster, HIV, Influenza, cholera, tuberculosis, pneumonia, viral diseases, epidemic and pandemic diseases",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70629.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70629.xml",downloadPdfUrl:"/chapter/pdf-download/70629",previewPdfUrl:"/chapter/pdf-preview/70629",totalDownloads:186,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"June 17th 2019",dateReviewed:"October 9th 2019",datePrePublished:"December 24th 2019",datePublished:"April 8th 2020",dateFinished:null,readingETA:"0",abstract:"Drosophila melanogaster is a widely used, dynamic model organism to study various pathogenic diseases observed ubiquitously in the human population. Drosophila, at present, is extensively used to conduct preclinical studies besides its counterpart rodents. The epidemic and pandemic diseases are discussed in this review to demonstrate Drosophila melanogaster as a key model. Epidemic and pandemic diseases are still claiming more than 5 million lives every year, and these diseases were well studied in flies. Currently there is no cure for the disease like HIV; the bacterial and fungal infections usually seen in HIV/AIDS patients could be demonstrated elaborately in Drosophila melanogaster. Diseases like myocardial infractions and cancer causing viral infection are long term effects of ART (anti-retroviral therapy) that could be experimented in flies. Stable Drosophila S2 cell line, Transgenic flies, transfusion of bacteria and fungi could be implemented to study several infectious diseases and for vaccine development. The latest trends in understanding pathogenic diseases and its potential biochemical markers in flies are discussed in this review to utilize the fruit flies as a functional tool and to explore further it in drug development. The advantages and disadvantages of the fly as a model of infection are discussed along with the epidemiology and the cellular pathophysiology",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70629",risUrl:"/chapter/ris/70629",book:{slug:"animal-models-in-medicine-and-biology"},signatures:"Saikat Samadder",authors:[{id:"192502",title:"Dr.",name:"Saikat",middleName:null,surname:"Samadder",fullName:"Saikat Samadder",slug:"saikat-samadder",email:"saikat.samadder46@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Epidemic disease",level:"2"},{id:"sec_2_2",title:"1.2 Pandemic disease",level:"2"},{id:"sec_3_2",title:"1.3 Vaccination",level:"2"},{id:"sec_4_2",title:"1.4 Global requirement",level:"2"},{id:"sec_5_2",title:"1.5 Fruit fly as a model organism for drug screening",level:"2"},{id:"sec_7",title:"2. Epidemiology of infectious diseases",level:"1"},{id:"sec_7_2",title:"2.1 Lower respiratory tract infection epidemiology",level:"2"},{id:"sec_8_2",title:"2.2 Influenza",level:"2"},{id:"sec_9_2",title:"2.3 Pneumonia and viral pneumonia",level:"2"},{id:"sec_10_2",title:"2.4 Tuberculosis",level:"2"},{id:"sec_11_2",title:"2.5 HIV",level:"2"},{id:"sec_12_2",title:"2.6 Diarrhoeal disease",level:"2"},{id:"sec_12_3",title:"2.6.1 Cholera",level:"3"},{id:"sec_14_2",title:"2.7 Hepatitis",level:"2"},{id:"sec_15_2",title:"2.8 Typhoid",level:"2"},{id:"sec_16_2",title:"2.9 Malaria",level:"2"},{id:"sec_17_2",title:"2.10 Viral meningitis, viral encephalitis and hemorrhagic fever viruses",level:"2"},{id:"sec_19",title:"3. Drosophila model to study highly infectious diseases",level:"1"},{id:"sec_20",title:"4. Host-pathogen interaction",level:"1"},{id:"sec_21",title:"5. Markers of infectious diseases",level:"1"},{id:"sec_22",title:"6. Behavioral and physiological characterization of infected flies",level:"1"},{id:"sec_22_2",title:"6.1 Negative geotaxis assay",level:"2"},{id:"sec_23_2",title:"6.2 Circadian rhythm",level:"2"},{id:"sec_24_2",title:"6.3 Wasting",level:"2"},{id:"sec_26",title:"7. Factors contributing to suitable infection model",level:"1"},{id:"sec_26_2",title:"7.1 Route of inoculum",level:"2"},{id:"sec_27_2",title:"7.2 Flies gender selection",level:"2"},{id:"sec_29",title:"8. In-vivo models for epidemic and pandemic diseases",level:"1"},{id:"sec_29_2",title:"8.1 HIV models",level:"2"},{id:"sec_30_2",title:"8.2 Influenza infection models",level:"2"},{id:"sec_31_2",title:"8.3 Pneumococcal pneumonia models",level:"2"},{id:"sec_32_2",title:"8.4 Tuberculosis models",level:"2"},{id:"sec_33_2",title:"8.5 Cholera models",level:"2"},{id:"sec_35",title:"9. Importance of in-vitro model infection in Drosophila",level:"1"},{id:"sec_36",title:"10. In-vitro model of epidemic and pandemic infectious disease",level:"1"},{id:"sec_37",title:"11. Viral meningitis, encephalitis and hemorrhagic fever S2 cell line model",level:"1"},{id:"sec_38",title:"12. Disadvantages of Drosophila model for drug screening",level:"1"},{id:"sec_39",title:"13. Future perspective",level:"1"},{id:"sec_40",title:"14. Conclusions",level:"1"},{id:"sec_41",title:"Acknowledgments",level:"1"},{id:"sec_44",title:"Conflict of interest",level:"1"},{id:"sec_41",title:"Notes/Thanks/Other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'Green MS, Swartz T, Mayshar E, Lev B, Leventhal A, Slater PE, et al. When is an epidemic an epidemic? Israel Medical Association Journal. 2002;4(1):3-6'},{id:"B2",body:'World Health Organization. Managing epidemics: Key facts about major deadly diseases. 2018. ISBN 978-92-4-156553-0'},{id:"B3",body:'Hays JN. Epidemics and Pandemics: Their Impacts on Human History. ABC-CLIO. 2005. 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PLoS One. 2011;6(11):e28349. DOI: 10.1371/journal.pone.0028349'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Saikat Samadder",address:"saikat.samadder46@gmail.com;, saikat.samadder24@gmail.com",affiliation:'
Dum Dum Motijheel, Kolkata, India
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1. Introduction
Antibiotic resistant bacteria are rapidly emerging worldwide [1]. The various biological active heterocyclic compounds, the indole derivatives are the key structural feature commonly found in natural products [2, 3] and bioactive molecules, such as tryptophan [4], tryptamine [5], and auxin [6]. Furthermore, it has been reported that sharing of the indole 3-carbon in the formation of spiroindoline derivatives highly enhances biological activity [7]. Moreover, some of the compounds containing benzenesulfonamide moiety also show broad spectrum biological properties such as elastase inhibitors [8], carbonic anhydrase inhibitors [9], clostridium histolyticum collogenase inhibitors [10] as well as herbicides and plant growth regulators [11]. Sulfonamides are common motifs in many drugs and medicinal compounds and play an important role in their bioactivity since the development of sulfa antibiotics in the 1930s [12]. Common drugs such as glibenclamide [13], sultiame [14], and COX-II inhibitors Piroxicam [15], Ampiroxicam [16], and Celecoxib [17] containing a sulfonyl moiety, which displays potential activity across a variety of biological targets. The sulfonamides are organic sulfur compounds which have attracted the attention for their better pharmacological activity [18, 19, 20]. It is interesting to note that the sulfonamide containing moiety is known to have some biological and pharmaceutical properties, such as, antitumor, antibacterial, thrombin inhibition, and antifungal activities [21, 22, 23].
In view of the above considerations, in continuation of our previous work on triazoles, pyrimidine, thiazoles and thiazolidinones of pharmaceutical interest [24, 25, 26, 27, 28, 29, 30] we report here on the synthesis and anticancer activity of new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide analogs.
2. Results and discussion
2.1 Chemistry
The aim of this work was to design and synthesize a novel series of benzenesulfonamide incorporating biologically active indoline moieties to evaluate their anticancer activity. We have synthesized new derivatives containing sulfonamide linkage in frame work. The synthetic methods adopted for the preparation of the N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide derivatives (5a-g) in Figure 1. We herein report the synthesis of new substituted sulfonamide derivatives with the aim of investigating their anticancer activity (Table 2). The synthetic methods adopted for the preparation of the title compounds (5a-g) are presented below. We have tried to develop simplified reaction conditions for all the steps by avoiding costly reagents, tedious purifications and longer reactions times, we have screened peptide coupling condition in Table 1 to obtain better yield, good purity, shorter reaction time, avoiding costly reagents and mainly reproducibility of yields.
For synthesis of compound 2 was done by using 1 treated with sulfonyl chloride at 0°C in DCM for 30 min and at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the obtained gummy material was washed with excess of n-hexane. The material was crystallized using 20% ethyl acetate: n-hexane mixture, no purification was required and the pure compound is obtained as yellow solid. This was used further used for sulfonamide reaction.
For the synthesis of compounds from 3a-g by sulfonamide coupling, different substituted amines were coupled with 2 in presence of pyridine as base and DCM as solvent at room temperature for 4 h. The reaction mass was treated with cold 2N aqueous HCl and stirred for 30 min., the solid precipitates out in most of cases which was filtered and washed with cold diethyl ether and cold pentane, all the intermediates obtained were white solids. For intermediates 3a-g the reaction yield was 85–95%.
For synthesis of 4a-4g requires hydrolysis of 3a-g using lithium hydroxide, tetrahydrofuran and water at room temperature for 10 h. Work up of reactions were modified, and wash in basic conditions and later acidifying it to get desired product as white solids with required purity. The acids obtained were in pure state so that it can be directly used for next amide coupling with indoline. All reaction intermediates 4a-g yield up to 80–85%.
For synthesis of 5a-g we have done series of screenings by varying different coupling reagents, different bases, solvents and time. We have varied the equivalents of reagents and bases used to get better yield and purity by avoiding column purifications. The results of screenings are explained in Table 1. In entry 1 and 2 we have used 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) as coupling reagent and DMF as solvent we have varied bases triethylamine and diisopropylethylamine after 14 h we got product 57 and 55% respectively. In entries 3 and 4 we have used benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as coupling reagent and THF as solvent and TEA and DIPEA as base to obtain yields 45 and 50% respectively. In entries 5, 6, 7, and 8 we have used the EDCI and hydroxybenzotriazole (HOBt) as coupling reagents with DMF as solvent along with TEA and DIPEA as base in entries 5 and 6 we have used 2.5 equiv. of base and in entries 7 and 8 we have increased base as 4 equiv. for 14 h. The yields obtained are 62, 72, 78, and 67% respectively. Same results like entry 1 and 2 are obtained in entry 9 and 10 when we used propylphosphonic anhydride (T3P) as coupling reagent and TEA and DIPEA as bases in DCM to get 50 and 60% yield respectively. In entry 11 it was observed that when EDCI (1.5 equiv.) when used along with DIPEA (2.5 equiv.) in DCM the yields was 95%, highlighted bold in Table 1. Work up requires extraction, and later on washing with 2N aqueous hydrochloric acid (HCl) to obtain solid compounds. Which was washed with 5% DCM: hexane, cold diethyl ether and cold pentane gives the desired compounds in yield highest yields and with 95% and above purity for 5a-g. We have not used HOBt in entry 11 and 90% yield obtain after 10 h only. The advantage of peptide coupling screenings are no need of column chromatography, no costly reagents required, no prep purification required. All obtained compounds are with 95% and above purity and are directly used for anticancer testing.
2.2 Biological evaluation: anticancer activity
The synthesized compounds were evaluated for their in vitro anticancer activity against human lung cancer cell line (A549), cervical (HeLa) cancer cell line, breast cancer cell line (MCF-7) and prostate cell line (DU-145) using 5-fluorouracil as reference drug [31].
5-Flourouracil is used for anal, breast, colorectal, esophageal, stomach, pancreatic and skin cancers mainly. The response parameter calculated was the IC50 value, which corresponds to the concentration required for 50% inhibition of cell viability. The results are presented in Table 2, where all compounds exhibit moderate to good activity compared to 5-fluorouracil as positive control. In the case of the human lung cancer cell line (A549) compounds 4a, 4b, 4d, 4f, 5d, and 5g were the most potent, with IC50 values ranging from 1.98 to 2.82 μM. On the HeLa cell line the compounds which showed potent activity were 4b, 4d, 5d, and 5g (IC50 = 1.99–2.92 μM). In case of the MCF-7 breast cancer cell line, the potent compounds were 4d, 5d, and 5g with IC50 activity of 2.12–2.52 μM. Lower activity was observed for the synthesized compounds on the Du-145 prostate cancer cell line, where the most potent candidates were compounds 5g with IC50 activity in the range of 2.12 μM. Generally, the lung (A549) and cervical (HeLa) cancer cell lines were the most sensitive to the synthesized compounds. With regard to broad spectrum anticancer activity, close examination of the data presented in Table 2, reveals that compounds 4b, 4d, and 5g were the most active, showing effectiveness toward the four cell lines. The structure activity relationship (SAR) can be explained on the basis of substitutions on both the aromatic rings less hindered substitution like methyl and ethyl on ortho and para position of rings increases the anticancer activity in all four cell lines, interestingly ortho triflouromethyl and indoline group decreases the anticancer activity and despite steric hindrance 4b, 4d, 5d, and 5g shows promising activity because of electron donating tendency. Most of the compounds show promising anticancer activity with electron donating groups on the ring than electron withdrawing groups.
Compound
A549 (lung cancer cell)
HeLa (cervical cancer cell)
MCF-7 (breast cancer cell)
Du-145 (prostate cancer cell)
4a
1.98 ± 0.12
3.83 ± 0.16
3.52 ± 0.06
3.86 ± 0.16
4b
2.81 ± 0.13
2.92 ± 0.08
2.32 ± 0.22
3.82 ± 0.12
4c
4.81 ± 0.12
6.32 ± 0.04
4.32 ± 0.06
3.73 ± 0.12
4d
2.82 ± 0.11
1.99 ± 0.22
2.36 ± 0.12
3.52 ± 0.11
4e
3.86 ± 0.08
4.38 ± 0.06
3.63 ± 0.12
6.52 ± 0.22
4f
2.72 ± 0.11
3.87 ± 0.08
4.12 ± 0.06
3.86 ± 0.22
4g
3.14 ± 0.14
3.98 ± 0.12
4.86 ± 0.11
4.57 ± 0.11
5a
8.48 ± 0.14
9.12 ± 0.08
7.82 ± 0.08
9.12 ± 0.06
5b
3.82 ± 0.08
4.13 ± 0.12
3.13 ± 0.11
3.52 ± 0.08
5c
4.13 ± 0.12
5.16 ± 0.08
6.12 ± 0.12
4.52 ± 0.11
5d
2.06 ± 0.12
2.12 ± 0.08
2.52 ± 0.16
5.12 ± 0.08
5e
2.52 ± 0.11
3.52 ± 0.11
4.48 ± 0.08
4.08 ± 0.11
5f
4.48 ± 0.08
4.98 ± 0.11
5.17 ± 0.22
5.18 ± 0.18
5g
2.73 ± 0.08
2.12 ± 0.12
2.12 ± 0.08
2.12 ± 0.04
5-FU
1.61 ± 0.12
1.72 ± 0.18
1.81 ± 0.10
1.89 ± 0.12
Table 2.
In vitro anticancer screening of the synthesized compounds against four cell lines, data are expressed as IC50 (μM) SD (n = 3).
2.3 General experimental procedure for the synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)
2.3.1 Step-1: preparation of ethyl 3-(chlorosulfonyl)benzoate (2)
To a stirred solution of ethyl benzoate (10 g, 67 mmol) in DCM (25 mL). RM was cooled to 0°C and chloro sulfonic acid (9 g, 73 mmol) was added drop wise and stirred for 1 h at same temperature followed by stirring at room temperature for 1 h. After completion of reaction, evaporate reaction mixture under reduced pressure and obtained gummy material is washed with excess of hexane and it is crystalized from 20% ethyl acetate: hexane mixture to obtain white solid as ethyl 3-(chlorosulfonyl)benzoate (2) which is used further for sulfonamide coupling reaction. Yield 54 g (81%).
2.3.2 Step-2: preparation of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g)
To a stirred solution of ethyl 3-(chlorosulfonyl)benzoate (2) (3 g, 10.1 mmol) in DCM (5 ml) was added pyridine (5 ml) the mixture was stirred at room temperature for 10 min. RM was cooled to 0°C and 2-methyl aniline (1.6 g, 15.16 mmol) was added drop wise followed by stirring at room temperature for 3 h. The reaction was monitored by TLC and LCMS, after completion of reaction poured reaction mass on cold 2N aqueous HCl (10 ml) and stirred RM it for 30 min. Precipitation formed in RM. Filtered the obtained solid and wash it with excess of water and cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate 2 as white solid. Yield 2.8 g (90%).
2.3.3 Step-3: preparation of 3-(N-(o-tolyl)sulfamoyl)benzoic acid (4a-g)
To a stirred solution of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g) (2 g, 5.40 mmol) in THF (10 ml) added water (2 ml), and lithium hydroxide (0.377 g, 18.2 mmol) and stirred reaction mixture for 4 h. Progress reaction was monitored by TLC and LCMS. After the completion of reaction evaporate reaction mixture under reduced pressure to obtain gummy material. Added 10 ml of water in it and extracted it with diethyl ether (10 ml). Collected aqueous layer and adjust its pH to 4 by using 6N aqueous HCl. Precipitation occurs stirred it for 30 min. Filtered the obtained solid and wash it with excess of water, cold diethyl ether (10 ml) and cold pentane (10 ml) to obtain desired 3-(N-(o-tolyl)sulfamoyl)benzoic acid 4a as white solids. Yield 1.6 g (90%).
The compound 3-(N-(o-tolyl)sulfamoyl)benzoic acid 4a-g (0.2 g, 0.65 mmol) was treated with EDCI (0.188 g, 0.98 mmol), DIPEA (0.34 ml, 1.96 mmol) in DCM (10 ml). Then added 2,4-dimentyl aniline (0.238 g, 1.96 mmol) and stirred RM at room temperature for 4 h. The reaction was monitored by TLC. Added 10 ml of cold water and stirred for 10 min, then extracted it with 10 ml of DCM. Collected organic layer wash it with 1N aqueous HCl and washed with brine (10 ml). To evaporate the organic layer to obtained the compound with 90% purity (5a-g). Purification done by washing with 5:95% of DCM: hexane. Obtained solid washed with cold diethyl ether (20 ml) and cold pentane (20 ml) to obtain compounds (5a-g). N-(2,4-dimethylphenyl)-3-(N-(o-tolyl)sulfamoyl)benzamide (5a): (0.240 g, 90%) as white solid, LC-MS m/z (%): 395 (M + H). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.70 (s, 1H), 8.26 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8 Hz, 1H), 7.7 (d, J = 8 Hz, 1H), 7.18–7.13 (m, 2H), 7.1–7.08 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.95–6.92 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). HPLC-98.25% RT-5.68 min. 13C NMR (CDCl3, 100 MHZ): 17.65, 17.79, 20.54, 126.09, 126.38, 126.40, 126.43, 126.58, 129.23, 129.42, 130.82, 130.89, 131.38, 133.42, 133.62, 134.27, 134.65, 135.40, 135.41, 135.45, 141.09, 163.93.
3. Conclusion
An effective method was developed which provided an easy access to a new series N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g) analogs. The mild reaction conditions, good to excellent yields, ease of workup and easily available substrates make the reactions attractive for the preparation of compounds. The compounds (4b, 4d, 5d, and 5g) show potent anticancer activity in all the four cell lines tested. The compounds are easy, simple and reproducible to synthesize in normal conditions and no additional conditions or expensive chemicals are required for the reaction. The cell-lines with maximum IC50 values are the important in the study.
Acknowledgments
The authors are thankful to the Head, Department of Chemistry, Deogiri college, Aurangabad for the laboratory facility.
\n',keywords:"indoline, sulfonamide, anticancer",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68172.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68172.xml",downloadPdfUrl:"/chapter/pdf-download/68172",previewPdfUrl:"/chapter/pdf-preview/68172",totalDownloads:252,totalViews:0,totalCrossrefCites:0,dateSubmitted:"June 27th 2018",dateReviewed:"June 18th 2019",datePrePublished:"July 17th 2019",datePublished:"June 10th 2020",dateFinished:null,readingETA:"0",abstract:"A highly efficient protocol was developed for the synthesis of 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide analogs with excellent yields. The new 3-(indoline-1-carbonyl)-N-(substituted) benzene sulfonamide derivatives (4a-g and 5a-g) were evaluated in vitro anticancer activity against a series of different cell lines like A549 (lung cancer cell), HeLa (cervical), MCF-7 (breast cancer cell) and Du-145 (prostate cancer cell) respectively. The results of the anticancer activity data revealed that most of the tested compounds showed IC50 values from 1.98 to 9.12 μM in different cell lines. Compounds 4b, 4d, 5d, and 5g were the most potent, with IC50 values ranging from 1.98 to 2.72 μM in different cell lines.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68172",risUrl:"/chapter/ris/68172",signatures:"Dattatraya Navnath Pansare and Rohini Narayan Shelke",book:{id:"8410",title:"Heterocycles",subtitle:"Synthesis and Biological Activities",fullTitle:"Heterocycles - Synthesis and Biological Activities",slug:"heterocycles-synthesis-and-biological-activities",publishedDate:"June 10th 2020",bookSignature:"B. P. Nandeshwarappa and Sadashiv S. 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Results and discussion",level:"1"},{id:"sec_2_2",title:"2.1 Chemistry",level:"2"},{id:"sec_3_2",title:"2.2 Biological evaluation: anticancer activity",level:"2"},{id:"sec_4_2",title:"2.3 General experimental procedure for the synthesis of N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)",level:"2"},{id:"sec_4_3",title:"2.3.1 Step-1: preparation of ethyl 3-(chlorosulfonyl)benzoate (2)",level:"3"},{id:"sec_5_3",title:"2.3.2 Step-2: preparation of ethyl 3-(N-(o-tolyl)sulfamoyl)benzoate (3a-g)",level:"3"},{id:"sec_6_3",title:"2.3.3 Step-3: preparation of 3-(N-(o-tolyl)sulfamoyl)benzoic acid (4a-g)",level:"3"},{id:"sec_7_3",title:"2.3.4 Step-4: N-(substituted phenyl)-3-(indoline-1-carbonyl)benzenesulfonamide (5a-g)",level:"3"},{id:"sec_10",title:"3. Conclusion",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Walsh CT, Wencewicz TA. Prospects for new antibiotics: A molecule-centered perspective. 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DOI: 10.1016/j.bmc.2015.04.036'},{id:"B22",body:'Wang XL, Wan K, Zhou CH. Synthesis of novel sulfanilamide-derived 1,2,3-triazoles and their evaluation for antibacterial and antifungal activities. European Journal of Medicinal Chemistry. 2010;45:4631. DOI: 10.1016/j.ejmech.2010.07.031'},{id:"B23",body:'Zhang Z, Jeyakkumar P, Kumar KV, Zhou CH. Synthesis of novel sulfonamide azoles via C-N cleavage of sulfonamides by azole ring and relational antimicrobial study. New Journal of Chemistry. 2015;39:5776. DOI: 10.1039/C4NJ01932F'},{id:"B24",body:'Pansare DN, Shelke RN, Pawar CD. A facile synthesis of (Z)-2-((5-(4-chlorobenzylidene)-4-oxo-4,5-dihydrothiazol-2-yl)amino)substituted acid using microwave irradiation and conventional method. Letters in Organic Chemistry. 2017;14(7):517. DOI: 10.2174/1570178614666170524142722'},{id:"B25",body:'Pansare DN, Shelke RN, Shinde DB. 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DOI: 10.2174/1570180815666181004114125'},{id:"B29",body:'Pawar CD, Pansare DN, Shinde DB. Synthesis of new 3-(substituted phenyl)-N-(2-hydroxy-2-(substituted phenyl)ethyl)-N-methylthiophene-2-sulfonamide derivatives as antiproliferative agents. European Journal of Chemistry. 2018;9(1):13. DOI: 10.5155/eurjchem.9.1.13-21.1669'},{id:"B30",body:'Pawar CD, Pansare DN, Shinde DB. Synthesis and antiproliferative activity of 3-(substituted)-4,5,6,7-tetrahydro-6-(substituted)-1H-pyrazolo[3,4-c]pyridine derivatives. European Journal of Chemistry. 2017;8(4):400. DOI: 10.5155/eurjchem.8.4.400-409.1645'},{id:"B31",body:'Skehan P, Storeng R, Scudiero D, Monks A, McMohan J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. Journal of the National Cancer Institute. 1990;82:1107'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Dattatraya Navnath Pansare",address:"dattatraya.pansare7@gmail.com",affiliation:'
Department of Chemistry, Deogiri College, Aurangabad, MS, India
Department of Chemistry, Deogiri College, Aurangabad, MS, India
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They are designed as PTOBDME-choline [(C34H36O8)n─C5H13N]; PTOBEE-choline [(C26H20O8)n─C5H13N]; PTOBDME-ammonium [(C34H36O8)n─C5H13N]; PTOBEE-ammonium [(C26H20O8)n─C5H13N]; PTOBUME-amide (C33H33O9N)n; and PTOBEE-amide (C26H19O9N)n. Structural characterization is performed by NMR. Thermal behavior is studied by thermogravimetry (TG) and differential scanning calorimetry (DSC), showing all the polymers endothermic transition from crystal phase to liquid crystal mesophase. Chirality is determined by optical rotatory dispersion (ORD). The cationic cholesteric liquid crystal polymers described here have proved to act as nonviral vectors in gene therapy, transfecting DNA to the nucleus cell.",signatures:"Mercedes Pérez Méndez",authors:[{id:"205972",title:"Dr.",name:"Mercedes",surname:"Pérez Méndez",fullName:"Mercedes Pérez Méndez",slug:"mercedes-perez-mendez",email:"perezmendez@ictp.csic.es"}],book:{title:"Liquid Crystals",slug:"liquid-crystals-recent-advancements-in-fundamental-and-device-technologies",productType:{id:"1",title:"Edited Volume"}}},{title:"Cholesteric Liquid Crystal Polyesteramides: Non-Viral Vectors",slug:"cholesteric-liquid-crystal-polyesteramides-non-viral-vectors",abstract:"Polyesteramides PNOBDME (C34H38N2O6)n, Poly[oxy(1,2-dodecane)-oxy-carbonyl-1,4-phenylene-amine-carbonyl-1,4-phenylene-carbonyl-amine-1,4-phenylene-carbonyl], and PNOBEE (C26H22N2O6)n, Poly[oxy(1,2-butylene)-oxy-carbonyl-1,4-phenylene-amine-carbonyl-1,4-phenylene-carbonyl-amine-1,4-phenylene-carbonyl], have been designed and synthesized as cholesteric liquid crystals (LCs)—through a condensation reaction between 4- 4′-(terephthaloyl-diaminedibenzoic chloride) (NOBC) and racemic glycol, DL-1,2-dodecanediol or DL-1,2-butanediol, respectively—as chemical modifications of multifunctional cholesteric LC polyesters, involving new properties but holding the precursor helical macromolecular structures. The new compounds have been characterized by 1H and 13C-NMR, COSY and HSQC, exhibiting two 1H-independent sets of signals observed for each enantiomer, attributed to two diastereomeric conformers, gg and gt, of the torsion containing the asymmetric carbon atom in the spacer. They have also been characterized by x-ray diffraction with synchrotron radiation source. Thermal behaviour of the new compounds is studied by thermogravimetric (TG) and differential scanning calorimetry (DSC) analysis. The substitution of the ester groups in the mesogen by amide groups causes an increase of thermal stability with respect to the precursors. Optical rotatory dispersion (ORD) is evaluated. Morphology of powdered PNOBDME exhibits spherical clusters of about 5 μm in diameter homogeneously dispersed. Molecular models show helical polymeric chains with stereoregular head-tail, isotactic structure, explained as due to the higher reactivity of the primary hydroxyl with respect to the secondary one in the glycol through the polycondensation reaction. Besides being biocompatible, these synthetic polyesteramides have proved to act as non-viral vectors in gene therapy and be able to transfect DNA to the nucleus cell. Similar new cationic cholesteric liquid crystal polyesters have also been synthesized in our laboratory.",signatures:"Mercedes Pérez Méndez and José Fayos Alcañiz",authors:[{id:"205972",title:"Dr.",name:"Mercedes",surname:"Pérez Méndez",fullName:"Mercedes Pérez Méndez",slug:"mercedes-perez-mendez",email:"perezmendez@ictp.csic.es"},{id:"316150",title:"Prof.",name:"José",surname:"Fayos Alcañíz",fullName:"José Fayos Alcañíz",slug:"jose-fayos-alcaniz",email:"pepefa1111@gmail.com"}],book:{title:"Liquid Crystals and Display Technology",slug:"liquid-crystals-and-display-technology",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"29799",title:"Dr.",name:"Carlos Gabriel",surname:"Avendaño",slug:"carlos-gabriel-avendano",fullName:"Carlos Gabriel Avendaño",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/29799/images/5221_n.jpg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"45521",title:"Prof.",name:"Kais A. 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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
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We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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