Abstract
Benzimidazoles are a class of heterocyclic, aromatic compounds which share a fundamental structural characteristic of six-membered benzene fused to five-membered imidazole moiety. Molecules having benzimidazole motifs showed promising application in biological and clinical studies. Nowadays it is a moiety of choice which possesses many pharmacological properties extensively explored with a potent inhibitor of various enzymes involved in a wide range of therapeutic uses which are antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, and antihistamine, as well as used in cardiovascular disease, neurology, endocrinology, ophthalmology, and more. The increased interest for benzimidazole compounds has been due to their excellent properties, like increased stability, bioavailability, and significant biological activity. This book chapter mainly discussed recent synthetic methods developed for the benzimidazole derivatives and their pharmacological properties exemplified on several derivatives.
Keywords
- benzimidazole
- heterocycle
- medicinal chemistry
- structure activity relationship
- biological activity
1. Introduction
The biological application of benzimidazole nucleus is discovered way back 1944, when Woolley speculated that benzimidazoles resemble purine-like structure and elicit some biological application [1]. Hence benzimidazole structure found isosters of naturally occurring nucleotides, which allows them to contact easily with the biopolymers of the living system. Later, Brink discovered 5,6-dimethylbenzimidazole as a degradation product of vitamin B12 and subsequently found some of its analogs having vitamin B12-like activity [2, 3]. These initial study reports emerged to explore various decorated benzimidazole motif discoveries by the medicinal chemist. Over the few decades of active research, benzimidazole has evolved as an important heterocyclic nucleus due to its wide range of pharmacological applications. Hence, it’s worth to understand the basic chemistry and structure of such a wonderful molecule. Benzimidazole is formed by the fusion of benzene and imidazole moiety, and numbering system according to the IUPAC is depicted in Figure 1. Historically, the first benzimidazole was prepared in 1872 by Hoebrecker, who obtained 2,5 (or 2,6)-dimethylbenzimidazole by the reduction of 2-nitro-4-methylacetanilide [4]. Benzimidazoles which contain a hydrogen atom attached to nitrogen in the 1-position readily tautomerize, and this may be depicted in Figure 1. This basic “6 + 5” heterocyclic structure is shared by another class of chemical compounds existing in nature shown in Figure 2. Among the members of this group of molecules are well-known building blocks for biopolymers, such as adenine and guanine, two of the five nucleic acid bases, uric acid, and caffeine. From this basic structural similarity, it is not too surprising that benzimidazole nucleus has emerged biologically as an important pharmacophore with a privileged structure in medicinal chemistry. Nowadays it is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is
The use of benzimidazole started many years back in 1990 onward, a vast number of benzimidazole analogs synthesis were reported, which resulted in increased stability, bioavailability, and significant biological activity. Some of the well-known active drugs with benzimidazole ring are mentioned in Figure 3, omeprazole, bendamustine, albendazole, and mebendazole. This chapter is mainly focused on the chemistry of the benzimidazoles and on the recently reported synthesis and mechanisms, structural aspects, and pharmacological applications with biological and clinical studies.
2. Overview of benzimidazole synthesis
Experimentally the simple method for the synthesis of benzimidazole derivatives begin with benzene containing nitrogen functions at
2.1 Synthesis of benzimidazoles by the reaction of substituted aldehyde with OPD
The reaction of OPD with aromatic/aliphatic aldehyde under suitable condition for the synthesis of 2-substituted benzimidazoles is well-known. Since the reaction involved oxidation, it required oxidative condition. The oxidation reaction may be carried out in the presence of air or more conveniently by oxidizing agent such as cupric acetate first introduced by Weidenhagen [14, 15, 16]. This method reported the reaction of OPD with aldehyde in the presence of water or alcoholic solution in the presence of cupric acetate. The formed cuprous salt of benzimidazole is decomposed with hydrogen sulfide which gave free benzimidazole after filtration. This method isolated excellent yields of 2-substituted benzimidazoles of alkyl, aryl, and heterocyclic substituted moiety. Further Wright’s group reported the synthesis of
2.2 Synthesis of benzimidazoles by the reaction of aryl/alkyl/heterocyclic acid chloride with OPD
Other synthetic routes involved carboxylic acid with an OPD-required harsh condition in the presence of a strong acid at elevated temperatures with poor yield reported for the benzimidazole. Alternatively, a two-step synthesis is reported, wherein the OPD is treated with one equivalent of an acid chloride derivative and the resulting mono-acylated product is subjected to cyclodehydration under various conditions such as heating in aqueous acids/solvents or by greener methods such as glycerol [35], ionic liquid [Hbim] BF4 [36], agro-waste extract WEPBA [37], heteropolyacid [38], BF3.Et2O [39], zeolite [40], KF-Al2O3 [41], and more (Figure 7).
2.3 Synthesis of benzimidazoles by the reaction of substituted alcohol or amines with o -nitroarylamines
Researcher demonstrated alternative substrate
2.4 Synthesis of benzimidazoles by the reaction of aldehyde or EAA with o -substituted arylamines
One-pot three-component reaction of 2-haloanilines, aldehydes, and NaN3 is also reported for the synthesis of benzimidazole [45]. The reaction catalyzed CuCl (5 mol%), and 5 mol% of TMEDA was reacted in DMSO at 120°C which gave the product good yields (
2.5 Synthesis of benzimidazoles by C-H amination of N -substituted amidines
Researcher demonstrated oxidative C-H amination of
2.6 Functionalization of benzimidazole to 2-substituted (hetero)aryl benzimidazole
Shao et al. recently reported the synthesis of benzimidazoles via direct C−H bond arylation in the presence of a NHC-Pd(II)-Im complex. The method is tolerable to various activated and deactivated (hetero)aryl chlorides to get 2-(hetero)aryl benzimidazoles in high yields. It is a facile and an alternative methodology for the direct C−H bond arylation of (
2.7 Synthesis by the reaction of N -substituted formamides with OPD derivatives
Bhanage et al. demonstrated efficient and convenient one-pot protocol synthesis of a benzimidazole derivative using various OPD derivatives and
2.8 Synthesis by one-pot three-component reaction
Punniyamurthy’s group reported copper-catalyzed one-pot, three-component reaction of
2.9 Synthesis of 1,2-disubstituted benzimidazole
Chang et al. demonstrated intramolecular C−H amidation using molecular iodine under basic conditions. The imine substrates required were readily prepared by condensation of aldehydes with OPD derivatives. The reaction is carried out in the absence of metal-free cyclization, works well with crude imines, and allows synthesis of series of
3. Pharmacological profile of benzimidazole derivatives
Benzimidazole moiety came in scenic after discovery of it as an integral part of the structure of the vitamin B12 in the 1950s. In the early 1960s, it was developed as plant fungicides and later as veterinary anthelminthic. Further, a variety of veterinary anthelmintics were developed and marketed, including parbendazole, fenbendazole, oxfendazole, and cambendazole. In 1962 the first benzimidazole developed and licensed for human use was thiabendazole, and present more derivatives of benzimidazole that have been clinically approved are albendazole, mebendazole, and flubendazole as anthelmintic; omeprazole, lansoprazole, and pantoprazole as proton pump inhibitors; astemizole as antihistaminic; enviradine as antiviral; and candesartan cilexetil and telmisartan as antihypertensives. In literature various substituted derivatives of benzimidazole demonstrated various therapeutic agents such as anticancer, antiproliferative, antimicrobials, antivirals, antiparasites, anthelmintic activity, anticonvulsant, antioxidants, anti-inflammatory, antihypertensive, immunomodulators, proton pump inhibitors, anticoagulants, hormone modulators, and CNS stimulants as well as antidepressants, antidiabetics, anti-HIV, lipid level modulators, etc. and have made an important scaffold for the development of new therapeutic agents (Figure 15) [10, 12, 13, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79].
3.1 Anticancer activity
Yang et al. optimized the solubility problem of lead benzimidazole (
3.2 Antiviral activity
Benzimidazole and its derivatives showed antiviral activity via contact with different virus particles such as human cytomegalovirus (HCMV), human herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and hepatitis-B and hepatitis-C virus (HBV and HCV). Luo et al. demonstrated the hepatitis-B virus inhibition by novel benzimidazole derivatives (
4. Conclusions
The modern drug discovery more emphasizes on benzimidazole nucleus containing pharmacophore extensively applied in the biological and clinical studies. In this book chapter reviewed, recent optimized synthetic methods reported by various research groups for the synthesis of benzimidazole derivatives are exemplified. Further, the therapeutic use of benzimidazole in important areas such as antidiabetic, anticancer, antimicrobial, antiparasitic, analgesics, antiviral, antihistamine, and more is discussed. In spite of the active, exhaustive, and target-based research on the development of many drug-like molecule development, the number of molecules that made its way to the market and clinic is not measurable. It can be probably due to lack of a comprehensive compilation of various research reports in each activity capable of giving an insight into the SAR of the compounds. The biological profiles of these new generations of benzimidazole would represent a fruitful matrix for further development of better medicinal agents.
Acknowledgments
I would like to thank my PhD students for contributing to this book chapter in experimental and literature collection. The authors thank the University Grants Commission and DST-FIST, New Delhi, India, VGST-GoK, for the financial support to establish research laboratory and instrumental facility. Author is also grateful to the host university, RCUB, for financial and infrastructure support.
Conflict of interest
The authors confirm that this book chapter content has no conflicts of interest.
Abbreviations
2-PrOH | 2-propanol |
AcOH | acetic acid |
ABTS | 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) |
CAN | ceric ammonium nitrate |
CH3CN | acetonitrile |
Cu(OAc)2 | cupric acetate |
CuCl | copper chloride |
CuI | |
DCM | dichloromethane |
DMF | N,N-dimethylformamide |
DMSO | dimethyl sulfoxide |
DPPH | 2,2-diphenyl-1-picrylhydrazyl |
EtOH | ethanol |
EAA | ethyl acetoacetate |
H2O2 | hydrogen peroxide |
H5IO6-SiO2 | silica-supported periodic acid |
HCl | |
HCOOH | formic acid |
HFIP | 1,1,1,3,3,3-hexafluoro-2-propanol |
I2 | |
KOH | potassium hydroxide |
KOtBu | potassium tertiary butoxide |
m-CPBA | m-chloroperoxybenzoic acid |
NaN3 | sodium azide |
NH4Cl | ammonium chloride |
OPD | o-phenylenediamine |
PhI(OAc)2 | benzene (diacetoxyiodo) |
PhI | |
PMHS | poly(methylhydrosiloxane) |
r.t | |
SAR | structure activity relationship |
TBHP | tert-butyl hydroperoxide |
TMEDA | N,N,N’,N’-tetramethylethylenediamine |
TMSN3 | trimethylsilyl azide |
TsOH | p-toluene sulfonic acid |
WEPBA | water extract of papaya bark ash |
Zn(OAc)2 | zinc acetate |
References
- 1.
Woolley DW. Some biological effects produced by benzimidazole and their reversal by purines. The Journal of Biological Chemistry. 1944; 152 :225-232 - 2.
Brink NG, Flokers K. Vitamin-B12. Vi. 5,6-Dimethylbenzimidazole, a degradation product of vitamin-B12. Journal of the American Chemical Society. 1949; 71 :2951. DOI: 10.1021/ja01176a532 - 3.
Epstein SS. Effect of some benzimidazoles on a vitamin B12-requiring alga. Nature. 1960; 188 :143-144. DOI: 10.1038/188143a0 - 4.
Wright JB. Chemistry of benzimidazoles. Chemical Reviews. 1951; 48 :397-541. DOI: 10.1021/cr60151a002 - 5.
McKellar QA, Scott EW. The benzimidazole anthelmintic agents—A review. Journal of Veterinary Pharmacology and Therapeutics. 1990; 13 :223-247. DOI: 10.1111/j.1365-2885.1990.tb00773.x - 6.
Spasov AA, Yozhitsa IN, Bugaeva LI, Anisimova VA. Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties (a review). Pharmaceutical Chemistry Journal. 1999; 33 :232-243. DOI: 10.1007/BF02510042 - 7.
Rossignol JF, Maisonneuve H. Benzimidazoles in the treatment of trichuriasis: A review. Annals of Tropical Medicine and Parasitology. 1984; 78 :135-144. DOI: 10.1080/00034983.1984.11811787 - 8.
Patil A, Ganguly S, Surana S. A systematic review of benzimidazole derivatives as an antiulcer agent. Rasayan Journal of Chemistry. 2008; 1 :447-460 - 9.
Boiani M, Gonzalez M. Imidazole and benzimidazole derivatives as chemotherapeutic agents. Mini Reviews in Medicinal Chemistry. 2005; 5 :409-424. DOI: 10.2174/1389557053544047 - 10.
Narasimhan B, Sharma D, Kumar P. Benzimidazole: A medicinally important heterocyclic moiety. Medicinal Chemistry Research. 2012; 21 :269-283. DOI: 10.1007/s00044-010-9533-9 - 11.
Sivakumar R, Pradeepchandran R, Jayaveera KN, Kumarnallasivan P, Vijaianand PR, Venkatnarayanan R. Benzimidazole: An attractive pharmacophore in medicinal chemistry. International Journal of Pharmaceutical Research. 2011; 3 :19-31 - 12.
Geeta Y, Swastika G. Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. European Journal of Medicinal Chemistry. 2015; 97 :419-443. DOI: 10.1016/j.ejmech.2014.11.053 - 13.
Yogita B, Om S. The therapeutic journey of benzimidazoles: A review. Bioorganic & Medicinal Chemistry. 2012; 20 :6208-6236. DOI: 10.1016/j.bmc.2012.09.013 - 14.
Hofmann K. Imidazole and its Derivatives Part-1. New York: Wiley Interscience; 1953 - 15.
Preston PN. Synthesis, reactions, and spectroscopic properties of benzimidazoles. Chemical Reviews. 1974; 74 (3):279-314. DOI: 10.1021/cr60289a001 - 16.
John BW. The chemistry of the benzimidazoles. Chemical Reviews. 1951; 48 :398-541. DOI: 10.1021/cr60151a002 - 17.
James GS, Isaac H. Organic redox reactions during the interaction of o-phenylenediamine with benzaldehyde. Tetrahedron Letters. 1971; 38 :351-3544 - 18.
Veeranagaiah V, Rao NVS, Ratnam CV. Studies in the formation of heterocyclic rings containing nitrogen. Proceedings of the Indian Academy of Science, Section A. 1974; 79 :230-235. DOI: doi.org/10.1007/BF03051324 - 19.
Liyan F, Wen C, Lulu K. Highly chemoselective synthesis of benzimidazoles in Sc(OTf)3-catalyzed system. Heterocycles. 2015; 91 :2306. DOI: 10.3987/COM-15-1332 - 20.
Heravi MM, Derikvand F, Ranjbar L. Sulfamic acid-catalyzed, three-component, one-pot synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives. Synthetic Communications. 2010; 40 :677-685. DOI: 10.1080/00397910903009489 - 21.
Bahrami K, Khodaei MM, Kavianinia I. H2O2/HCl as a new and efficient system for synthesis of 2-substituted benzimidazoles. Journal of Chemical Research. 2006; 12 :783-784. DOI: 10.3184/030823406780199730 - 22.
Ma H, Han X, Wang Y, Wang J. A simple and efficient method for synthesis of benzimidazoles using FeBr3 or Fe(NO3)3·9H2O as catalyst. ChemInform. 2007; 38 :49. DOI: 10.1002/chin.200749146 - 23.
Du L-H, Wang Y-G. A rapid and efficient synthesis of benzimidazoles using hypervalent iodine as oxidant. Synthesis. 2007; 5 :675-678. DOI: 10.1055/s-2007-965922 - 24.
Venkateswarlu Y, Kumar SR, Leelavathi P. Facile and efficient one-pot synthesis of benzimidazoles using lanthanum chloride. Organic and Medicinal Chemistry Letters. 2013; 3 :7. DOI: 10.1186/2191-2858-3-7 - 25.
Sontakke VA, Ghosh S, Lawande PP, Chopade BA, Shinde VS. A simple, efficient synthesis of 2-aryl benzimidazoles using silica supported periodic acid catalyst and evaluation of anticancer activity. ISRN Organic Chemistry. 2013:1-7. DOI: 10.1155/2013/453682 - 26.
Martins GM, Puccinelli T, Gariani RA, Xavier FR, Silveira CC, Mendes SR. Facile and efficient aerobic one-pot synthesis of benzimidazoles using Ce(NO3)3·6H2O as promoter. Tetrahedron Letters. 2017; 58 :1969-1972. DOI: 10.1016/j.tetlet.2017.04.020 - 27.
Kumar KR, Satyanarayana PVV, Reddy BS. NaHSO4-SiO2 promoted synthesis of benzimidazole derivatives. Archives of Applied Science Research. 2012; 4 :1517-1521 - 28.
Rombi M, Dick PR. Chemical Abstracts. 1972; 80 :108526s. FR2178385 - 29.
Harnish H. Chemical Abstracts. 1975; 83 :79240y. DE2346316 - 30.
Bhatnagar KS, George MV. Oxidation with metal oxides-II: Oxidation of chalcone phenylhydrazones, pyrazolines, o-aminobenzylidine anils and o-hydroxy benzylidine with MnO2. Tetrahedron. 1968; 24 :1293-1298 - 31.
Moumita S, Asish RD. I2/TBHP promoted oxidative C-N bond formation at room temperature: Divergent access of 2-substituted benzimidazoles involving ring distortion. Tetrahedron Letters. 2018; 59 :2520-2525. DOI: 10.1016/j.tetlet.2018.05.028 - 32.
Bhenki C, Karhale S, Helavi V. 5-Sulfosalicylic acid as an efficient organocatalyst for environmentally benign synthesis of 2-substituted benzimidazoles. Iranian Journal of Catalysis. 2016; 6 :409-413 - 33.
Gan Z, Tian Q , Shang S, Luo W, Dai Z, Wang H, et al. Imidazolium chloride-catalyzed synthesis of benzimidazoles and 2-substituted benzimidazoles from o-phenylenediamines and DMF derivatives. Tetrahedron. 2018; 74 :7450-7456. DOI: 10.1016/j.tet.2018.11.014 - 34.
Chakraborty A, Debnath S, Ghosh T, Maiti DK, Majumdar S. An efficient strategy for N-alkylation of benzimidazoles/imidazoles in SDS-aqueous basic medium and N-alkylation induced ring opening of benzimidazoles. Tetrahedron. 2018; 74 :5932-5941. DOI: 10.1016/j.tet.2018.08.029 - 35.
Bachhav HM, Bhagat SB, Telvekar VN. Efficient protocol for the synthesis of quinoxaline, benzoxazole and benzimidazole derivatives using glycerol as green solvent. Tetrahedron Letters. 2011; 52 :5697-5701. DOI: 10.1016/j.tetlet.2011.08.105 - 36.
Nadaf RN, Siddiqui SA, Daniel T, Lahoti RJ, Srinivasan K. Room temperature ionic liquid promoted regioselective synthesis of 2-aryl benzimidazoles, benzoxazoles and benzothiazoles under ambient conditions. Journal of Molecular Catalysis A: Chemical. 2014; 214 :155-160. DOI: 10.1016/j.molcata.2003.10.064 - 37.
Kantharaju K, Hiremath PB. One-pot, green approach synthesis of 2-aryl substituted benzimidazole derivatives catalyzed by water extract of papaya bark ash. Asian Journal of Chemistry. 2018; 30 :1634-1638. DOI: 10.14233/ajchem.2018.21296 - 38.
Heravi MM, Sadjadi S, Oskooie HA, Shoar RH, Bamoharram FF. Heteropolyacids as heterogeneous and recyclable catalysts for the synthesis of benzimidazoles. Catalysis Communications. 2008; 9 :504-507. DOI: 10.1016/j.catcom.2007.03.011 - 39.
Tandon VK, Kumar M. BF3-Et2O promoted one-pot expeditious and convenient synthesis of 2-substituted benzimidazoles and 3,1,5-benzoxadiazepines. Tetrahedron Letters. 2004; 45 :4185-4187. DOI: 10.1016/j.tetlet.2004.03.117 - 40.
Heravi MM, Tajbakhsh M, Ahmadi NA, Mohajerani B. Zeolites. Efficient and eco-friendly catalysts for the synthesis of benzimidazoles. Monatshefte für Chemie. 2006; 137 :175-179. DOI: 10.1007/s00706-005-0407-7 - 41.
Khalili SB, Sardarian AR. KF/Al2O3: An efficient solid heterogeneous base catalyst in one-pot synthesis of benzimidazoles and bis-benzimidazoles at room temperature. Monatshefte fuer Chemie. 2012; 143 :841-846. DOI: 10.1007/s00706-011-0647-7 - 42.
Nguyen TB, Ermolenko L, Al-Mourabit A. Sodium sulfide: A sustainable solution for unbalanced redox condensation reaction between o-nitroanilines and alcohols catalyzed by an iron-sulfur system. Synthesis. 2015; 47 :1741-1748. DOI: 10.1055/s-0034-1380134 - 43.
Nguyen TB, Bescont JL, Ermolenko L, Mourabit AA. Cobalt- and iron-catalyzed redox condensation of o-substituted nitrobenzenes with alkylamines: A step- and redox-economical synthesis of diazaheterocycles. Organic Letters. 2013; 15 :6218-6221. DOI: 10.1021/ol403064z - 44.
Hanan EJ, Chan BK, Estrada AA, Shore DG, Lyssikatos JP. Mild and general one-pot reduction and cyclization of aromatic and heteroaromatic 2-nitroamines to bicyclic 2H-imidazoles. Synlett. 2010; 18 :2759-2764. DOI: 10.1002/chin.201111140 - 45.
Kim Y, Kumar MR, Park N, Heo Y, Lee S. Copper-catalyzed, one-pot three-component synthesis of benzimidazoles by condensation and C-N bond formation. The Journal of Organic Chemistry. 2011; 76 :9577-9583. DOI: 10.1021/jo2019416 - 46.
Bahrami K, Khodaei MM, Naali F. Mild and highly efficient method for the synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles. The Journal of Organic Chemistry. 2008; 73 :6835-6837. DOI: 10.1021/jo8010232 - 47.
Mayo MS, Yu X, Zhou X, Feng X, Yamamoto Y, Bao M. Convenient synthesis of benzothiazoles through Brønsted acid catalyzed cyclization of 2-amino thiophenols/anilines with β-diketones. Organic Letters. 2014; 16 :764-767. DOI: 10.1021/ol403475v - 48.
Alla SK, Kumar RK, Sadhu P, Punniyamurthy T. Iodobenzene catalyzed C-H amination of N-substituted amidines using m-chloroperbenzoic acid. Organic Letters. 2013; 15 :1334-1337. DOI: 10.1021/ol400274f - 49.
Baars H, Beyer A, Kohlhepp SV, Bolm C. Transition-metal-free synthesis of benzimidazoles mediated by KOH/DMSO. Organic Letters. 2014; 16 :536-539. DOI: 10.1021/ol403414v - 50.
Gu Z-S, Chen W-X, Shao L-X. N-Heterocyclic carbene-palladium(II)-1-methylimidazole complex-catalyzed direct C-H bond arylation of (benz)imidazoles with aryl chlorides. The Journal of Organic Chemistry. 2014; 79 :5806-5811. DOI: 10.1021/jo5010058 - 51.
Nale DB, Bhanage BM. N-Substituted formamides as C1-sources for the synthesis of benzimidazole and benzothiazole derivatives by using zinc catalysts. Synlett. 2015; 26 :2831-2834. DOI: 10.1055/s-0035-1560319 - 52.
Mahesh D, Sadhu P, Punniyamurthy T. Copper(I)-catalyzed regioselective amination of N-aryl imines using TMSN3 and TBHP: A route to substituted benzimidazoles. The Journal of Organic Chemistry. 2015; 80 :1644-1650. DOI: 10.1021/jo502574u - 53.
Mahesh D, Sadhu P, Punniyamurthy T. Copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines and sodium azide using TBHP: A route to 2-substituted benzimidazoles. The Journal of Organic Chemistry. 2016; 81 :3227-3234. DOI: 10.1021/acs.joc.6b00186 - 54.
Hu Z, Zhao T, Wang M, Wu J, Yu W, Chang J. I2-mediated intramolecular C-H amidation for the synthesis of N-substituted benzimidazoles. The Journal of Organic Chemistry. 2017; 82 :3152-3158. DOI: 10.1021/acs.joc.7b00142 - 55.
Medzhitov R. Inflammation 2010: New adventures of an old flame. Cell. 2010; 140 :771-776. DOI: 10.1016/j.cell.2010.03.006 - 56.
Gulcan HO, Mavideniz A, Sahin MF, Orhan IE. Benzimidazole-derived compounds designed for different targets of Alzheimer’s disease. Current Medicinal Chemistry. 2019. DOI: 10.2174/0929867326666190124123208. E-pub Abstract Ahead of Print - 57.
Dilip D, Tai-Lin C, Yi-wen L, Tsai-Yi Y, Ming-Hsi W, Tung-Hu T, et al. Novel N-mustard-benzimidazoles/benzothiazoles hybrids, synthesis and anticancer evaluation. Anti-Cancer Agents in Medicinal Chemistry. 2017; 17 :1741-1755. DOI: 10.2174/1871520617666170522120200 - 58.
Ritchu S, Sandeep J, Sandeep A, Deepika S, Neelam J. Synthesis, characterization and molecular Docking studies of novel N-(benzimidazol-1-ylmethyl)-4-chlorobenzamide analogues for potential anti-inflammatory and antimicrobial activity. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry. 2018; 17 :16-31. DOI: 10.2174/1871523017666180426125141 - 59.
Gurmeet S, Yogita B, Gulshan B, Kumar R, Design G. Synthesis and PASS assisted evaluation of novel 2-substituted benzimidazole derivatives as potent anthelimintics. Medicinal Chemistry. 2014; 10 :418-425. DOI: 10.2174/157340641004140421115518 - 60.
Prasanna AD, Saleel AL. Design and synthesis of mannich bases as benzimidazole derivatives as analgesic agents. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry. 2015; 14 :35-46. DOI: 10.2174/1871523014666150312164625 - 61.
Ibrahim HS, Albakri ME, Mahmoud WR, Allam HA, Reda AM, Abdel-Aziz HA. Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase. Bioorganic Chemistry. 2019; 85 :337-348. DOI: 10.1016/j.bioorg.2019.01.006 - 62.
Wu Z, Bao XL, Zhu WB, Wang YH, Phuong Anh NT, Wu XF, et al. Design, synthesis, and biological evaluation of 6-benzoxazole benzimidazole derivatives with antihypertension activities. ACS Medicinal Chemistry Letters. 2018; 10 :40-43. DOI: 10.1021/acsmedchemlett.8b00335 - 63.
Salehi N, Mirjalili BBF, Nadri H, Abdolahi Z, Forootanfar H, Samzadeh-Kermani A, et al. Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer’s agents. Bioorganic Chemistry. 2018; 83 :559-568. DOI: 10.1016/j.bioorg.2018.11.010 - 64.
Bharadwaj SS, Poojary B, Nandish SKM, Kengaiah J, Kirana MP, Shankar MK, et al. Efficient synthesis and in silico studies of the benzimidazole hybrid scaffold with the quinolinyloxadiazole skeleton with potential α-glucosidase inhibitory, anticoagulant, and antiplatelet activities for type-II diabetes mellitus management and treating thrombotic disorders. ACS Omega. 2018; 3 :12562-12574. DOI: 10.1021/acsomega.8b01476 - 65.
Mostafa AS, Gomaa RM, Elmorsy MA. Design and synthesis of 2-phenyl benzimidazole derivatives as VEGFR-2 inhibitors with anti-breast cancer activity. Chemical Biology & Drug Design. 2019; 93 :454-463. DOI: 10.1111/cbdd.13433 - 66.
Vlaminck J, Cools P, Albonico M, Ame S, Ayana M, Bethony J, et al. Comprehensive evaluation of stool-based diagnostic methods and benzimidazole resistance markers to assess drug efficacy and detect the emergence of anthelmintic resistance: A Starworms study protocol. PLoS Neglected Tropical Diseases. 2018; 12 :e0006912. DOI: 10.1371/journal.pntd.0006912 - 67.
Al-Blewi FF, Almehmadi MA, Aouad MR, Bardaweel SK, Sahu PK, Messali M, et al. Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents. Chemistry Central Journal. 2018; 12 :110. DOI: 10.1186/s13065-018-0479-1 - 68.
Asati V, Ghode P, Bajaj S, Jain SK, Bharti SK. 3D-QSAR and molecular docking studies on oxadiazole substituted benzimidazole derivatives: Validation of experimental inhibitory potencies towards COX-2. Current Computer-Aided Drug Design. 2018. DOI: 10.2174/1573409914666181003153249 - 69.
Bistrović A, Krstulović L, Stolić I, Drenjančević D, Talapko J, Taylor MC, et al. Synthesis anti-bacterial and anti-protozoal activities of amidinobenzimidazole derivatives and their interactions with DNA and RNA. Journal of Enzyme Inhibition and Medicinal Chemistry. 2018; 33 :1323-1334. DOI: 10.1080/14756366.2018.1484733 - 70.
Hussain A, AlAjmi MF, Rehman MT, Khan AA, Shaikh PA, Khan RA. Evaluation of transition metal complexes of benzimidazole-derived scaffold as promising anticancer chemotherapeutics. Molecules. 2018; 23 :pii: E1232. DOI: 10.3390/molecules23051232 - 71.
Gangrade A, Pathak V, Augelli-Szafran CE, Wei HX, Oliver P, Suto M, et al. Preferential inhibition of Wnt/β-catenin signaling by novel benzimidazole compounds in triple-negative breast cancer. International Journal of Molecular Sciences. 2018; 19 :pii: E1524. DOI: 10.3390/ijms19051524 - 72.
Al Ajmi MF, Hussain A, Rehman MT, Khan AA, Shaikh PA, Khan RA. Design, synthesis, and biological evaluation of benzimidazole-derived biocompatible copper(II) and zinc(II) complexes as anticancer chemotherapeutics. International Journal of Molecular Sciences. 2018; 19 :pii: E1492. DOI: 10.3390/ijms19051492 - 73.
Akhtar MJ, Khan AA, Ali Z, Dewangan RP, Rafi M, Hassan MQ , et al. Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors. Bioorganic Chemistry. 2018; 78 :158-169. DOI: 10.1016/j.bioorg.2018.03.002 - 74.
Koronkiewicz M, Chilmonczyk Z, Kazimerczuk Z, Orzeszko A. Deoxynucleosides with benzimidazoles as aglycone moiety are potent anticancer agents. European Journal of Pharmacology. 2018; 820 :146-155. DOI: 10.1016/j.ejphar.2017.12.018 - 75.
Ajani OO, Tolu-Bolaji OO, Olorunshola SJ, Zhao Y, Aderohunmu DV. Structure-based design of functionalized 2-substituted and 1,2-disubstituted benzimidazole derivatives and their in vitro antibacterial efficacy. Journal of Advanced Research. 2017; 8 :703-712. DOI: 10.1016/j.jare.2017.09.003 - 76.
Liu HB, Gao WW, Tangadanchu VKR, Zhou CH, Geng RX. Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation. European Journal of Medicinal Chemistry. 2018; 143 :66-84. DOI: 10.1016/j.ejmech.2017.11.027 - 77.
Bistrović A, Krstulović L, Harej A, Grbčić P, Sedić M, Koštrun S, et al. Design, synthesis and biological evaluation of novel benzimidazole amidines as potent multi-target inhibitors for the treatment of non-small cell lung cancer. European Journal of Medicinal Chemistry. 2018; 143 :1616-1634. DOI: 10.1016/j.ejmech.2017.10.061 - 78.
Farahat AA, Ismail MA, Kumar A, Wenzler T, Brun R, Paul A, et al. Indole and benzimidazole bichalcophenes: Synthesis, DNA binding and antiparasitic activity. European Journal of Medicinal Chemistry. 2018; 143 :1590-1596. DOI: 10.1016/j.ejmech.2017.10.056 - 79.
Abdelgawad MA, Bakr RB, Omar HA. Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents. Bioorganic Chemistry. 2017; 74 :82-90. DOI: 10.1016/j.bioorg.2017.07.007 - 80.
Xiang P, Zhou T, Wang L, Sun CY, Hu J, Zhao YL, et al. Novel benzothiazole, benzimidazole and benzoxazole derivatives as potential antitumor agents: Synthesis and preliminary in vitro biological evaluation. Molecules. 2012; 17 :873-883. DOI: 10.3390/molecules17010873 - 81.
Gowda NR, Kavitha CV, Chiruvella KK, Joy O, Rangappa KS, Raghavan SC. Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents. Bioorganic & Medicinal Chemistry Letters. 2009; 19 :4594-4600. DOI: 10.1016/j.bmcl.2009.06.103 - 82.
Omar MA, Shaker YM, Galal SA, Ali MM, Kerwin SM, Li J, et al. Synthesis and docking studies of novel antitumor benzimidazoles. Bioorganic & Medicinal Chemistry. 2012; 20 :6989-6901. DOI: 10.1016/j.bmc.2012.10.010 - 83.
Liu T, Sun C, Xing X, Jing L, Tan R, Luo Y, et al. Synthesis and evaluation of 2-[2-(phenylthiomethyl)-1H-benzo [d] imidazol-1-yl] acetohydrazide derivatives as antitumor agents. Bioorganic & Medicinal Chemistry Letters. 2012; 22 :3122-3125. DOI: 10.1016/j.bmcl.2012.03.061 - 84.
Karthikeyan C, Solomon VR, Lee H, Trivedi P. Synthesis and biological evaluation of 2-(phenyl)-3H-benzo[d] imidazole-5-carboxylic acids and its methyl esters as potent anti-breast cancer agents. Arabian Journal of Chemistry. 2017; 10 :S1788-S1794. DOI: 10.1016/j.arabjc.2013.07.003 - 85.
Yoon YK, Ali MA, Wei AC, Choon TS, Osman H, Parang K, et al. Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities. Bioorganic & Medicinal Chemistry. 2014; 22 :703-710. DOI: 10.1016/j.bmc.2013.12.029 - 86.
El-Nassan HB. Synthesis antitumor activity and SAR study of novel [1 2 4] triazino [4 5-a] benzimidazole derivatives. European Journal of Medicinal Chemistry. 2012; 53 :22-27. DOI: 10.1016/j.ejmech.2012.03.028 - 87.
Singh M, Tandon V. Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Arylsubstituted 2-bis-1H-benzimidazoles. European Journal of Medicinal Chemistry. 2011; 46 :659-669. DOI: 10.1016/j.ejmech.2010.11.046 - 88.
Luo Y, Yao JP, Yang L, Feng CL, Tang W, Wang GF, et al. Design and synthesis of novel benzimidazole derivatives as inhibitors of hepatitis B virus. Bioorganic & Medicinal Chemistry. 2010; 18 :5048-5055. DOI: 10.1016/j.bmc.2010.05.076 - 89.
Gudmundsson KS, Sebahar PR, Richardson LD, Miller JF, Turner EM, Catalano JG, et al. Amine substituted N-(1H-benzimidazol-2ylmethyl)-5678-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1. Bioorganic & Medicinal Chemistry Letters. 2009; 19 :5048-5052. DOI: 10.1016/j.bmcl.2009.07.037 - 90.
Miller JE, Turner EM, Gudmundsson AS, Jenkinson S, Spaltenstein A, Thomsan N, et al. Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents. Bioorganic & Medicinal Chemistry Letters. 2010; 20 :2125-2128. DOI: 10.1016/j.bmcl.2010.02.053 - 91.
Beaulieu PL, Dansereau N, Duan J, Garneau M, Gillard J, McKercher G, et al. Benzimidazole thumb pocket I finger-loop inhibitors of HCV NS5B polymerase: Improved drug-like properties through C-2 SAR in three sub-series. Bioorganic & Medicinal Chemistry Letters. 2010; 20 :1825-1829. DOI: 10.1016/j.bmcl.2010.02.003 - 92.
Tonelli M, Simone M, Tasso B, Novelli F, Boido V, Sparatore F, et al. Antiviral activity of benzimidazole derivatives II antiviral activity of 2-phenylbenzimidazole derivatives. Bioorganic & Medicinal Chemistry. 2010; 18 :2937-2953. DOI: 10.1016/j.bmc.2010.02.037 - 93.
Wubulikasimu R, Yang Y, Xue F, Luo X, Shao D, Li Y, et al. Synthesis and biological evaluation of novel benzimidazole derivatives bearing a heterocyclic ring at 4/5 position. Bulletin of the Korean Chemical Society. 2013; 34 :2297-2304. DOI: 10.5012/bkcs.2013.34.8.2297 - 94.
Monforte A-M, Ferro S, Luca LD, Surdo GL, Morreale F, Pannecouque C, et al. Design and synthesis of N1-aryl-benzimidazoles 2-substituted as novel HIV-1 nonnucleoside reverse transcriptase inhibitors. Bioorganic & Medicinal Chemistry. 2014; 22 (4):1459-1467. DOI: 10.1016/j.bmc.2013.12.045