Nematicidal activity of 11(a–g).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"5755",leadTitle:null,fullTitle:"Diagnosis and Management of Head and Neck Cancer",title:"Head and Neck Cancer",subtitle:"Diagnosis and Management of",reviewType:"peer-reviewed",abstract:"This book includes useful and recent information to the readers regarding the following topics: Signs and symptoms and etiology and risk factors of head and neck cancer, Epidemiology and the role of microRNAs in nasopharyngeal carcinoma and oral carcinogenesis, History, classifications, and managements of salivary gland cancer, Considerations, classifications, and managements of thyroid gland cancer, Updates in the diagnosis and management of medullary thyroid carcinoma, Interventional techniques used for the relief of head and neck cancer pain, Oral side effects of head and neck irradiation, Health-related quality of life in maxillectomy patients rehabilitated with obturator prostheses",isbn:"978-953-51-3496-1",printIsbn:"978-953-51-3495-4",pdfIsbn:"978-953-51-4659-9",doi:"10.5772/65190",price:119,priceEur:129,priceUsd:155,slug:"diagnosis-and-management-of-head-and-neck-cancer",numberOfPages:168,isOpenForSubmission:!1,isInWos:1,hash:"b24fa372d58f381ff1747f9ee2d22d30",bookSignature:"Zuhre Akarslan",publishedDate:"September 6th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5755.jpg",numberOfDownloads:7732,numberOfWosCitations:2,numberOfCrossrefCitations:4,numberOfDimensionsCitations:9,hasAltmetrics:0,numberOfTotalCitations:15,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 19th 2016",dateEndSecondStepPublish:"November 10th 2016",dateEndThirdStepPublish:"April 2nd 2017",dateEndFourthStepPublish:"May 30th 2017",dateEndFifthStepPublish:"August 1st 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. 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During this time, she isolated and selected fungi with high cellulose activity for the enzymatic hydrolysis of sugarcane bagasse. \nShe received her Ph.D. in Science from the Soil Science Department (Agricultural Microbiology Program) at ESALQ/USP, with a period of one year as a visiting scholar at the University of California Berkeley and Energy Bioscience Institute. Meanwhile, she worked on the improvement of S. cerevisiae by hybridization for increased tolerance toward inhibitors from second-generation ethanol substrates.\nCurrently, she is Collaborating Professor of Cell Biology and Molecular Genetics at University of Sao Paulo. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7238",title:"Fuel Ethanol Production from Sugarcane",subtitle:null,isOpenForSubmission:!1,hash:"f3b4eb4ac5837543b99bd6e1a1a4cacc",slug:"fuel-ethanol-production-from-sugarcane",bookSignature:"Thalita Peixoto Basso and Luiz Carlos Basso",coverURL:"https://cdn.intechopen.com/books/images_new/7238.jpg",editedByType:"Edited by",editors:[{id:"139174",title:"Ph.D.",name:"Thalita",surname:"Peixoto Basso",slug:"thalita-peixoto-basso",fullName:"Thalita Peixoto Basso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8107",title:"Yeasts in Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"b3b86676fec9c1a1f34c8bd00b16c11c",slug:"yeasts-in-biotechnology",bookSignature:"Thalita Peixoto Basso",coverURL:"https://cdn.intechopen.com/books/images_new/8107.jpg",editedByType:"Edited by",editors:[{id:"139174",title:"Ph.D.",name:"Thalita",surname:"Peixoto Basso",slug:"thalita-peixoto-basso",fullName:"Thalita Peixoto Basso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67803",title:"Synthesis and Biological Evaluation of Novel Phosphonyl Thiazolo Pyrazoles",doi:"10.5772/intechopen.86977",slug:"synthesis-and-biological-evaluation-of-novel-phosphonyl-thiazolo-pyrazoles",body:'1,2,3-Triazoles are one of the most important classes of heterocyclic organic compounds, which are reported to present in a plethora of biological activities for diverse therapeutic areas [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]. The 1,2,3-triazole motif is associated with diverse pharmacological activities such as antibacterial, antifungal, hypoglycemic, antihypertensive and analgesic properties [13, 14, 15]. Polysubstituted five-membered aza heterocyclic’s rank the most potent glycosidase inhibitors [16, 17, 18, 19]. Further, this nucleus in combination with or in linking with various other classes of compounds such as amino acids, steroids, aromatic compounds, carbohydrates etc. became prominent in having various pharmacological properties [20]. 1,2,3-Triazole modified carbohydrates have became easily available after the discovery of the Cu(I) catalyzed azide-alkynes 1,3-dipolar cycloaddition reaction [21, 22, 23, 24, 25] and quickly became a prominent class of non-natural sugars. The chemistry and biology of triazole modified sugars is dominated by triazole glycosides [26]. Therefore, the synthesis and investigation of biological activity of 1,2,3-triazole glycosides is an important objective, which also received the considerable attention by the medicinal chemists.
Thiazoles are familiar group of heterocyclic compounds possessing a wide variety of biological activities and their utility as medicine is very much established [27]. Thiazole nucleus is also an integral part of all the available penicillins which have revolutionized the therapy of bacterial diseases [28]. The chemistry of thiazolidinone ring system is one of considerable interest as it is the core structure in various synthetic pharmaceuticals displaying a broad spectrum of biological activities [29]. The thiazolidinone nucleus also appears frequently in the structure of various natural products notably thiamine, compounds possessing cardiac and glycemic benefits such as troglitazone [30] and many metabolic products of fungi and primitive marine animals, including 2-(aminoallyl)-thiazole-4-carboxylic acids [31]. Numerous thiazolidinone derivatives have shown significant bio activities such as antidiarrhoeal [32], anticonvulsant [33], antimicrobial [34], antidiabetic [35], antihistaminic [36], anticancer [37], anti HIV [38], Ca2+ channel blocker [39], PAF antagonist [40], cardioprotective [41], antiischemic [42], COX inhibitory [43], antiplatelet activating factor [44], non-peptide thrombin receptor antagonist [45], tumor necrosis factor-α-antagonist [46] and nematicidal activities. Organophosphorus compounds continue to attract much attention because of their various potent biological activities [47, 48] in particular, phosphonates are important synthetic derivatives which can have often act as phosphate and carboxylic acid mimics, and interfere with enzymatic processes. Much of this activity has been attributed to the relatively inert nature of the C▬P bond [47, 48], which is not easily hydrolyzed as compared to the P▬O bond found in phosphates. The synthesis and biological activities of important natural and nonnatural phosphonate derivatives, including phosphonated aza heterocyclics and nucleotides, have been reviewed [49, 50, 51]. In view of the importance of heterocyclics bearing a phosphonate group, new synthetic methods that would allow straightforward access to these versatile building blocks are needed [47, 48, 52]. Among the various bioactive heterocyclics the pyrazole moiety remains of great interest because of its wide applications in the pharmaceutical and agrochemical industry [53, 54]. In addition, pyrazoles also play a central role in coordination chemistry [55].
Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invasion by secondary pathogens [56]. Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest. The nematicide use is slated for reduction due to environmental problems, and human and animal health concern. For example, effective nematicides such as dibromochloropropane (DBCD) and ethylene dibromide (EDB) have been withdrawn from the market due to their deleterious effects on human and the environment. Methyl bromide, the most effective and widely used fumigant for soil borne pests including nematodes, has already been banned.
The use of nonfumigant nematicides, based on organophosphates and carbamates, is expected to increase the withdrawal of methyl bromide, which will bring about new environmental concerns. In fact, the highly toxic aldicarb used to control insects and nematodes has been detected in ground water [57]. Therefore alternative nematode control methods or less toxic nematicides need to be developed [58]. One way of searching for such nematicidal compounds is to screen naturally occurring compounds in plants. Several such compounds, e.g., alkaloids, phenols, sesquiterpenes, diterpenes, polyacetylenes, and thienyl derivatives have nematicidal activity [59]. For example, α-terthienyl is a highly effective nematicidal compound [60]. Other compounds with nematicidal activity have been isolated from plants, mainly from the family Asteraceae [59]. However, compounds of plant origin and their analogs have not been developed into commercial nematicides; hence there is a need to develop commercial synthesis.
Following the successful introduction of nematicidal agents, inspired by the biological profile of triazoles, thiazoles, Phosponylpyrazoles. In continuation of our work on biological active molecules [61, 62, 63, 64, 65, 66, 67, 68, 69] it was thought to interest to accommodate all those moieties in single molecular frame work. In this article we wish to report the synthesis of a new class of hybrid heterocyclic’s 11a–g in good yields and their evaluated nematicidal activity.
The key intermediate, 8 required for the synthesis of title compound was prepared according to the procedure outlined in Figure 1. Diacetyl-D-glucal (2) prepared from 3,4,6-tri-O-acetyl D-glucal by treating with triethyl silane and boron trifluoride diethyl etherate, de acylation of 2, with NaOMe in methanol at 0°C for 1 hour gave 3 (77%), which on subsequent treatment with TBDMSCl in dichloromethane in presence of NEt3 for 12 hours afforded TBS ether 4 (80%), on treatment with propargyl bromide in toluene in presence of tetra butyl ammonium hydrogen sulfate produced di ether 5. After deprotection of TBS ether the propargyl ether converted into triazole 7 (82%) by using 1,3-dipolar cycloaddition with p-chloro phenyl azide was carried out at ambient temperature in the presence of CuSO4 and sodium ascorbate in a mixture of 1:1 CH2Cl2-H2O. Oxidation of 7 with IBX in acetonitrile afforded compound 8. Subsequently one pot synthesis of triazole linked thiazolidinone glycosides was carried out by the condensation reaction between 8, primary aromatic amine and a thio glycolic acid in presence of ZnCl2 under microwave irradiation (Figure 1). The reaction is completed in only 5–10 minutes and the compounds, isolated by conventional work-up, (9a–g) are obtained in satisfactory yields, Compound 9a–g was then reacted with p-fluoro benzaldehyde in presence of anhydrous NaOAc in glacial AcOH at reflux temperature gave chalcone derivatives of triazole linked thiazolidinone glycosides 10a–g, on cyclocondensation under conventional and microwave irradiation with Bestmann-Ohira reagent in presence of anhydrous KOH gave compounds 11(a–g). The structures of synthesized compounds were confirmed by IR, NMR, MS and elemental analysis. Further the compounds were subject to nematicidal activity testing.
R= (a) C6H5; (b) 4-Cl-C6H5; (c) 4-NO2-C6H5; (d) 2-CH3-C6H5; (e) 4-CH3-C6H5; (f) 3-OH-C6H5; (g) 2-OH-C6H5.
The compounds synthesized 10a-g in this study were also screened for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique [70] at various concentrations. The nematicidal activity of each test compound was compared with the standard drug Levamisole. The results have been expressed in terms of LD50 i.e., median lethal dose at which 50% nematodes became immobile (dead). The screened data reveal that, compounds 11b, 11c, 11f and 11g are the most effective against Dietylenchus myceliophagus and Caenorhabditis elegans the other test compounds showed moderate activity. The LD50 values of the test compounds screened are presented in Table 1.
Compound | LD50 value (ppm) | |
---|---|---|
D. myceliophagus | C. elegans | |
11a | 740 | 860 |
11b | 220 | 280 |
11c | 320 | 270 |
11d | 501 | 540 |
11e | 960 | 900 |
11f | 209 | 210 |
11g | 310 | 360 |
Levamisole | 160 | 180 |
Nematicidal activity of 11(a–g).
Commercial grade reagents were used as supplied. Solvents except analytical reagent grade were dried and purified according to literature when necessary. Di-methyl 2-oxopropyl phosphonate was purchased from Aldrich for the synthesis o Bestmann-Ohira reagent. Reaction progress and purity of the compounds were checked by thin-layer chromatography (TLC) on pre-coated silica gel F254 plates from Merck and compounds visualized either by exposure to UV light or dipping in 1% aqueous potassium permanganate solution. Silica gel chromatographic columns (60–120 mesh) were used for separations. Optical rotations were measured on a Perkin-Elmer 141 polarimeter by using a 2 ml cell with a path length of 1 dm with CHCl3 or CDCl3 as solvent. All melting points are uncorrected and measured using Fisher-Johns apparatus. IR spectra were recorded as KBr disks on a Perkin-Elmer FTIR spectrometer. Micro wave reactions are carried out in mini lab microwave catalytic reactor (ZZKD, WBFY-201). The 1HNMR and 13C NMR spectra were recorded on a Varian Gemini spectrometer (300 MHz for 1H and 75 MHz for 13C). Chemical shifts are reported as δ ppm against TMS as internal reference and coupling constants (J) are reported in Hz units. Mass spectra were recorded on a VG micro mass 7070H spectrometer. Elemental analysis (C, H, N) determined by a Perkin-Elmer 240 CHN elemental analyzer, were within ±0.4% of theoretical.
((2R,3S)-3-acetoxy-3,6-dihydro-2H-pyran-2-yl)methyl acetate (2): Tri-O-acetyl-D-glucal (1) (3.0 g, 11.02 mmol) was dissolved in anhydrous dichloromethane (5 ml). The solution was cooled to 0°C, triethyl silane (1.53 g, 13.22 mmol) was added and the mixture was stirred for 5 minutes. Next boron tri fluoride diethyl etherate (690 μl of a 40 w% solution in diethyl ether, 11.02 mmol) was added drop wise and the reaction mixture was stirred for 90 minutes. The mixture was poured into a saturated solution of NaHCO3. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica gel (PE/EtOAc, 3:1) yielded the title compound (2.24 g, 10.42 mmol, 95%) as a colorless syrup. [α]D20: +115.5 (c = 1.00, CHCl3).1HNMR (300 MHz, CDCl3): δ 5.87-5.84 (m, 2H, =CH),4.95 (t,1H, OCH),4.03-3.99 (m, 1H, CH),4.12-4.09 (m,4H, OCH2), 2.20 (s, 6H, COCH3);13C NMR (75 MHz, CDCl3): δ170.2, 127.2, 125.8, 73.6, 65.1, 64.0, 62.5, 21.1; MS: m/z (M++H) 215. Anal. Calcd for C10H14O5: C, 56.07; H, 6.59; Found: C, 55.82; H, 6.35.
(2R,3S)-2-((tert-butyldimethylsilyloxy)methyl)-3,6-dihydro-2H-pyran-3-ol (4): Diacetate 2 (17.22 mmol) was treated by a catalytic amount of sodium methoxide in methanol (100 ml) at room temperature. After evaporation of the solvent, the free hydroxyl unsaturated glycoside was obtained in quantitative yield and used without further purification. This diol was treated with 2.50 equiv. of TBD MSCl (3.14 g, 21.14 mmol), 2.6 equiv. of NEt3 (3.2 ml, 22.4 mmol), and 0.05 equiv. of imidazole (30 mg, 0.43 mmol) in CH2Cl2 (30 ml) at room temperature for ca. 24 hours (until TLC analysis showed no more starting material). After addition of 25 ml of water and extraction with 3–30 ml of CH2Cl2, the organic layer was dried. After evaporation of the solvent under reduced pressure, the residue was purified by column chromatography using petroleum ether/ethyl acetate as the eluent yielded the title compound (1.94 g, 10.42 mmol, 85%) as a colorless syrup. 1HNMR (300 MHz, CDCl3): δ 6.0–5.82 (m, 2H, 〓CH), 5.42 (d, J = 6.5 Hz, 1H, CH),4.50 (brs, 1H, OH), 4.20–4.12(m,1H, CH), 3.91–3.80(m,4H, CH2), 0.98 (s, 9H, t-Bu), 0.24 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.5, 125.6, 84.6, 81.5, 73.6, 62.7, 25.6, 18.1; MS: m/z (M++Na) 267. Anal. Calcd for C12H24O3Si: C, 58.97; H, 9.90; Found: C, 58.62; H, 9.75.
tert-butyldimethyl(((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl)methoxy)silane (5): To a solution of alcohol 4 (400 mg, 1.63 mmol, 1.0 equiv) in toluene (1.6 ml) was added a 35% aqueous solution of NaOH (1.6 ml), propargyl bromide (80% solution in toluene, 363 μl, 2.4 mmol, 1.5 equiv), and n-Bu4NHSO4 (280 mg, 0.82 mmol, 0.5 equiv). After 6 hours of vigorous stirring at room temperature, Et2NH (1.6 ml) was added. The reaction mixture was stirred for 1 hour, poured into ice water, cautiously neutralized by addition of a 3 M solution of hydrochloric acid, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (hexane/EtOAc 85:15) to afford propargyl ether as colorless oil (0.345 g, 75%). 1HNMR (300 MHz, CDCl3): δ 6.03–5.80 (m, 2H, 〓CH), 4.69 (t, J = 3.9 Hz 1H, CH), 3.68 (dd, J = 8.9 Hz, 4.1 Hz, 1H, OCH), 3.99–3.89(m, 6H, CH2), 3.20 (s, 1H, CH), 0.96 (s, 9H, t-Bu), 0.23 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ 127.2, 124.9, 78.0, 76.2, 74.2, 64.2, 63.2, 58.5, 25.3, 18.5; MS: m/z (M++H) 283. Anal. Calcd for C15H26O3Si: C, 63.78; H, 9.28; Found: C, 63.62; H, 8.95.
((2R,3S)-3-(prop-2-ynyloxy)-3,6-dihydro-2H-pyran-2-yl)methanol (6): To a stirred solution of 5 (0.325 g) in Tetra hydro furan catalytic amount of TBAF was added and stirred the reaction mixture at room temperature for 15 minutes, extracted the product with Ethyl acetate (20 ml). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60–120 mesh, hexane/EtOAc 70, 0) to afford alcohol as yellow oil (0.285 g, 85%) 1HNMR (300 MHzCDCl3) 5.95–5.75 (m, 2H, 〓CH), 4.65(d, J = 3.9 Hz, 1H, CH), 4.52 (brs, 1H, OH), 4.09–4.11 (m, 4H, OCH2), 3.64 (dd, J = 4.1 Hz, 8.9 Hz, 1H, OCH), 3.76 (d, J = 6.8 Hz, 2H, OCH2), 3.28 (s, 1H, CH): 13C NMR (75 MHz, CDCl3): δ 127.2, 125.6, 78.3, 76.1, 74.1, 64.2, 61.4, 58.0; MS: m/z (M++H) 169. Anal. Calcd for C9H12O3: C, 64.27; H, 7.10; Found: C, 64.02; H, 6.95.
((2R,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)methanol (7): To a solution containing alkyne 6 (0.250 g, 0.778 mmol), p-chloro phenyl azide (0.130 g, 0.849 mmol) in dichloromethane (10 ml) and water (10 ml) were added CuSO4.5H2O (0.110 g) and sodium ascorbate (0.114 g). The resulting suspension was stirred at room temperature for 6 hours. After this time, the mixture was diluted with 5 ml dichloromethane and 5 ml water. The organic phase was separated, dried with sodium sulfate and concentrated at reduced pressure the crude product was purified by column chromatography on silica gel (60–120 mesh, hexane/EtOAc 65:35) to afford 7 (0.290 g, 75%) as a white powder. Mp: 149–1510°C. 1HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.56 (d, J = 9.2 Hz, 2H, Ar-H),7.45 (d, J = 8.9 Hz, 2H, Ar-H), 5.85–5.79 (m, 2H, 〓CH), 4.59 (s, 2H, OCH2), 4.50 (brs, 1H, OH), 3.88–3.99 (m, 4H, OCH2), 3.8–3.75 (m, 2H, OCH): 13CNMR (75 MHz, CDCl3): δ140.9, 134.5, 134.1, 128.4, 127.5, 125.4, 122.1, 11.5, 78.6, 68.5, 65.7, 64.2, 62.4: MS: m/z (M++H) 322. Anal. Calcd for C15H16ClN3O3: C, 55.90; H, 5.01, N, 13.06; Found: C, 55.65, H, 4.95. N, 12.86.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one 9(a-g): To a solution of alcohol 7 (0.120 g, 0.465 mmol) in CH2Cl2 (5 ml), catalytic amount of IBX was added at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was filtered and washed with CH2Cl2 (2 × 10 ml). It was dried (Na2SO4) and evaporated to give aldehyde 7 (0.110 g) in quantitative yield as a yellow liquid, which was used as such for the next reaction.
To a stirred mixture of 8 (0.110 g, 0.373 mmol), aromatic amine (0.373 mmol) and anhydrous thioglycolic acid (0.140 g, 0.211 mmol) in dry toluene (5 ml), ZnCl2 (0.100 g, 0.751 mmol) was added after 2 minutes and irradiated in microwave bath reactor at 280 W for 4–7 minutes at 110°C. After cooling, the filtrate was concentrated to dryness under reduced pressure and the residue was taken-up in ethyl acetate. The ethyl acetate layer was washed with 5% sodium bicarbonate solution and finally with brine. The organic layer was dried over Na2SO4 and evaporated to dryness at reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexane-ethyl acetate as eluent.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-phenylthiazolidin-4-one (9a): mp: 157–159°C. Yield—75%. 1HNMR (300 MHz, CDCl3): δ8.04 (s, 1H, Ar-H), 7.50 (d, J = 9.2 Hz, 2H, Ar-H), 7.40 (d, J = 8.9 Hz, 2H, Ar-H), 7.10–6.20 (m, 5H, Ar-H), 5.80–5.71 (m, 2H, 〓CH), 4.90 (d, J = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2XCH), 3.79 (d, J = 6.6 Hz, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.4, 144.1, 141.8, 134.1, 128.2, 125.6, 122.4, 119.4, 85.6, 72.6, 66.4, 64.0, 51.4, 33.9: MS: m/z (M++H) 469. Anal. Calcd for C23H21ClN4O3S: C, 58.91; H, 4.51, N, 11.95; Found: C, 58. 68, H, 4.35. N, 11.66.
(R)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)thiazolidin-4-one (9b): mp: 226–228°C Yield—69%. 1HNMR (300 MHz, CDCl3): 8.05 (s, 1H, Ar-H), 7.54 (d, J = 9.4 Hz, 4H, Ar-H), 7.42 (d, J = 8.6 Hz, 4H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, J = 5.2 Hz, CH-S), 4.50 (s, 2H, OCH2), 4.06–3.96 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.72 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 144.2, 139.2, 134.2, 129.2, 125.5, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2, 34.1: MS: m/z (M++Na) 525. Anal. Calcd for C23H20Cl2N4O3S: C, 54.88; H, 4.00, N, 11.13; Found: C, 54.58, H, 3.75. N, 10.86.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-(4-nitrophenyl)thiazolidin-4-one (9c): mp: 211–213°C, Yield—71%. 1HNMR (300 MHz, CDCl3): δ8.26 (d, J = 8.7 Hz, 2H, Ar-H), 8.03 (s, 1H, Ar-H), 7.61 (d, J = 9.4 Hz, 2H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 6.84 (d, J = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, J = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, J = 6.9 Hz, 2H, OCH2), 3.82 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ171.5, 144.0, 141.8, 134.2, 128.5, 125.4, 119.5, 85.4, 72.4, 65.9, 63.6, 51.5, 34.6: MS: m/z (M++H) 514. Anal. Calcd for C23H20ClN5O5S: C, 53.75; H, 3.92, N, 13.63; Found: C, 53.58, H, 3.75. N, 13.39.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-o-tolylthiazolidin-4-one (9d): mp: 191–193°C, Yield—65%. 1HNMR (300 MHz, CDCl3): δ8.08 (s, 1H, Ar-H), 7.56 (d, J = 9.2 Hz, 2H, Ar-H), 7.49 (d, J = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, J = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 3.81 (s, 2H, CH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.2, 134.2, 130.7, 128.6, 125.6, 122.0, 119.5, 116.5, 85.4, 72.6, 65.8, 63.4, 52.0, 32.3, 17.5: MS: m/z (M++H) 483. Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C, 59.48, H, 4.55. N, 11.49.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-p-tolylthiazolidin-4-one (9e): mp: 195–198°C Yield—79%. 1HNMR (300 MHz, CDCl3): δ8.05 (s, 1H, Ar-H), 7.51 (d, J = 9.2 Hz, 2H, Ar-H), 7.45 (d, J = 8.7 Hz, 2H, Ar-H), 7.25 (d, J = 8.2 Hz, 2H, Ar-H), 6.84 (d, J = 9.4 Hz, 2H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.95 (s, 1H, CHS), 4.59 (s, 2H, OCH2), 4.04–3.99 (m, 2H, CH), 3.98 (t, 2H, OCH2), 3.90 (s, 2H, CH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.5, 144.2, 138.6, 136.2, 14.1, 133.2, 129.4, 127.5, 122.5, 119.5, 85.4, 72.0, 66.4, 63.5, 51.5, 34.0, 21.4: MS: m/z (M++H) 483. Anal. Calcd for C24H23ClN4O3S: C, 59.68; H, 4.80, N, 11.60; Found: C, 59.58, H, 4.65. N, 11.43.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-(3-hydroxyphenyl)thiazolidin-4-one (9f): mp: 218–219°C, Yield—85%. 1H-NMR (300 MHz, CDCl3): δ9.40 (brs, 1H, Ph-OH), 8.08 (s, 1H, Ar-H), 7.58 (d, J = 9.3 Hz, 2H, Ar-H), 7.49 (d, J = 8.6 Hz, 2H, Ar-H), 6.83–6.76 (m, 4H, Ar-H), 5.72–5.68 (m, 2H, 〓CH), 4.94 (d, J = 5.2 Hz, 1H, CHS), 4.64 (s, 2H, OCH2), 4.12 (t, 2H, OCH2), 4.01–3.94 (m, 2H, CH), 3.92 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ 170.5, 158.2, 143.8, 134.5, 130.4, 128.6, 125.6, 122.4, 119.5, 114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5, 34.1: MS: m/z (M++Na) 507. Anal. Calcd for C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.28, H, 4.65. N, 11.43.
(R)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-3-(4-hydroxyphenyl)thiazolidin-4-one (9g): mp: 273–275°C, Yield—82%. 1H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H), 7.56 (d, J = 9.2 Hz, 2H, Ar-H), 7.46 (d, J = 8.4 Hz, 2H, Ar-H), 7.32 (d, J = 8.6 Hz, 2H, Ar-H), 7.02 (d, J = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, J = 5.4 Hz, 1H, CHS), 4.66 (s, 2H, OCH2), 4.09 (d, J = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.94 (s, 2H, CH2): 13CNMR (75 MHz, CDCl3): δ170.9, 154.1, 144.4, 134.9, 134.8, 128.8, 127.2, 125.6, 123.2, 119.4, 116.4, 85.4, 72.6, 66.5, 64.0, 51.6, 34.5: MS: m/z (M++H) 485. Anal. Calcd for C23H21ClN4O4S: C, 59.96; H, 4.36, N, 11.55; Found: C, 59.38, H, 4.75. N, 11.33.
General procedure for the synthesis of (10a-g): A mixture of compound 9a (0.01 mol), p-fluoro benzaldehyde (0.02 mol) and sodium acetate (0.01 mol) in anhydrous glacial acetic acid (20 ml), was refluxed for 3 hours. The reaction mixture was concentrated and then poured into ice cold water, the solid thus separated, was filtered, washed with water and crystallized from glacial acetic acid. To afford pure 10a as yellow solid.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-phenylthiazolidin-4-one (10a): mp: 235–237°C, Yield—85%. 1HNMR (300 MHz, CDCl3): δ8.07 (s, 1H, Ar-H), 7.80 (s, 1H, CH〓C), 7.72 (d, J = 9.6 Hz, 2H, Ar-H), 7.40 (d, J = 9.2 Hz, 2H, Ar-H), 7.45 (d, J = 8.9 Hz, 2H, Ar-H), 7.19 (d, J = 8.2 Hz, 2H, Ar-H), 7.02–6.80 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.90 (d, J = 5.2 Hz, 1H, CH▬S), 4.52 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.79 (d, J = 6.6 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.4, 162.1, 144.1, 141.8, 139.8, 134.1, 130.4, 128.2, 125.6, 124.6, 122.4, 119.4, 115.5, 85.6, 72.6, 66.4, 64.0, 51: MS: m/z (M++H) 575. Anal. Calcd for C30H24ClFN4O3S: C, 62.66; H, 4.21, N, 9.74; Found: C, 62. 48, H, 4.15. N, 9.56.
(R,Z)-3-(4-chlorophenyl)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)thiazolidin-4-one (10b): mp: 216–218°C. Yield—72%. 1HNMR (300 MHz, CDCl3): 8.09 (s, 1H, Ar-H), 7.75 (s, 1H, CH〓C), 7.62 (d, J = 9.5 Hz, 2H, Ar-H), 7.52 (d, J = 9.4 Hz, 4H, Ar-H), 7.40 (d, J = 8.6 Hz, 4H, Ar-H), 7.19 (d, J = 8.1 Hz, 2H, Ar-H), 5.84–5.75 (m, 2H, 〓CH), 4.94 (d, J = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06–3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ170.5, 162.1, 144.2, 139.2, 134.2, 130.4, 129.2, 125.5, 124.1, 122.2, 119.4, 85.4, 72.8, 65.4, 63.4, 51.2: MS:m/z(M++Na)632. Anal. Calcd for C30H23Cl2 FN4O3S: C, 59.12; H, 3.80, N, 9.19; Found: C, 59.01, H, 3.45. N, 8.96.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-nitrophenyl)thiazolidin-4-one (10c): mp: 221–223°C Yield—75%. 1HNMR (300 MHz, CDCl3): δ8.29 (d, J = 8.7 Hz, 2H, Ar-H), 8.09 (s, 1H, Ar-H), 7.69 (d, J = 9.1 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.61 (d, J = 9.4 Hz, 2H, Ar-H), 7.46 (d, J = 8.5 Hz, 2H, Ar-H), 7.18 (d, J = 8.3 Hz, 2H, Ar-H), 6.84 (d, J = 9.8 Hz, 2H, Ar-H), 5.86–5.79 (m, 2H, 〓CH), 4.96 (d, J = 5.2 Hz, CH-S), 4.55 (s, 2H, OCH2), 4.05–3.95 (m, 2H, 2XCH), 3.85 (d, J = 6.9 Hz, 2H, OCH2): 13CNMR (75 MHz, CDCl3): δ171.5, 162.1, 144.0, 141.8, 134.2, 130.4, 128.5, 125.4, 119.5, 115.4, 85.4, 72.4, 65.9, 63.6, 51.5: MS: m/z (M++H) 620. Calcd for C30H23ClFN5O5S: C, 58.11; H, 3.74, N, 11.29; Found: C, 57.98, H, 3.55. N, 11.09.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-o-tolylthiazolidin-4-one (10d): mp: 201–203°C, Yield—85%. 1HNMR (300 MHz, CDCl3): δ8.08 (s, 1H, Ar-H), 7.69 (d, J = 8.5 Hz, 2H, Ar-H), 7.62 (s, 1H, CH〓C), 7.56 (d, J = 9.2 Hz, 2H, Ar-H), 7.49 (d, J = 8.7 Hz, 2H, Ar-H), 7.45–7.39 (m, 4H, Ar-H), 7.10 (d, J = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.93 (d, J = 5.2 Hz, 1H, CHS), 4.60 (s, 2H, OCH2), 4.05–3.96 (m, 2H, CH), 3.90 (t, 2H, OCH2), 2.1 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.8, 162.9, 144.6, 137.2, 133.2, 130.6, 130.4, 128.2, 125.9, 122.7, 119.2, 116.2, 115.4, 84.4, 72.1, 65.3, 63.1, 52.5, 32.0, 17.5: MS: m/z (M++H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51; Found: C, 62.75, H, 4.25. N, 9.29.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-p-tolylthiazolidin-4-one (10e): mp: 205–215°C, Yield—66%. 1HNMR (300 MHz, CDCl3): δ8.02 (s, 1H, Ar-H), 7.69 (s, 1H, CH〓C), 7.65 (d, J = 9.1 Hz, 2H, Ar-H), 7.54 (d, J = 9.2 Hz, 2H, Ar-H), 7.42 (d, J = 8.7 Hz, 2H, Ar-H), 7.35 (d, J = 8.2 Hz, 2H, Ar-H), 7.18 (d, J = 8.8 Hz, 2H, Ar-H), 6.80 (d, J = 9.4 Hz, 2H, Ar-H), 5.70–5.69 (m, 2H, 〓CH), 4.94 (s, 1H, CHS), 4.55 (s, 2H, OCH2), 4.04–3.98 (m, 2H, CH), 3.96 (t, 2H, OCH2), 2.32 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.1, 162.5, 144.1, 139.5, 137.6, 135.2, 133.2, 130.4, 129.1, 127.5, 124.1, 122.5, 119.5, 115.3, 85.1, 72.5, 66.1, 63.2, 51.2, 21.6: MS: m/z (M++H) 589. Anal. Calcd for C31H26ClFN4O3S: C, 63.21; H, 4.45, N, 9.51; Found: C, 62.98, H, 4.25. N, 9.33.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(3-hydroxyphenyl)thiazolidin-4-one (10f): mp: 218–219°C, Yield—82%. 1H-NMR (300 MHz, CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.08 (s, 1H, Ar-H), 7.71 (d, J = 9.7 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.59 (d, J = 9.3 Hz, 2H, Ar-H), 7.44 (d, J = 8.6 Hz, 2H, Ar-H), 7.15 (d, J = 8.4 Hz, 2H, Ar-H), 6.80–6.78 (m, 4H, Ar-H), 5.70–5.68 (m, 2H, 〓CH), 4.92 (d, J = 5.2 Hz, 1H, CHS), 4.64 (s, 2H, OCH2), 4.10 (t, 2H, OCH2), 4.01–3.98 (m, 2H, CH): 13CNMR (75 MHz, CDCl3): δ170.5, 162.1, 158.2, 143.8, 139.8, 134.5, 130.8, 128.6, 125.6, 124.1, 122.4, 119.5, 115.7, 114.8, 106.5, 85.4, 72.5, 66.4, 63.4, 51.5: MS: m/z (M++H) 591. Anal. Calcd for C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.85. N, 9.13.
(R,Z)-2-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-5-(4-fluorobenzylidene)-3-(4-hydroxyphenyl)thiazolidin-4-one (10g): mp: 283–285°C, Yield—62%. 1H-NMR (300 MHz,CDCl3): δ9.42 (brs, 1H, Ph-OH), 8.05 (s, 1H, Ar-H), 7.85 (d, J = 9.3 Hz, 2H, Ar-H), 7.65 (s, 1H, CH〓C), 7.56 (d, J = 9.2 Hz, 2H, Ar-H), 7.46 (d, J = 8.4 Hz, 2H, Ar-H), 7.32 (d, J = 8.6 Hz, 2H, Ar-H), 7.19 (d, J = 8.3 Hz, 2H, ArH), 7.02 (d, J = 8.8 Hz, 2H, Ar-H), 5.89–5.80 (m, 2H, 〓CH), 4.96 (d, J = 5.4 Hz, 1H, CHS), 4.66 (s, 2H, OCH2), 4.09 (d, J = 2H, OCH2), 4.04–3.98 (m, 2H, CH), 13CNMR (75 MHz, CDCl3): δ170.9, 162.5, 154.1, 144.4, 139.8, 134.9, 134.8, 130.4, 128.8, 127.2, 125.6, 123.2, 119.4, 116.4, 115.9, 85.4, 72.6, 66.5, 64.0, 51.6: MS: m/z (M++H) 591. Anal. Calcd for C30H24ClFN4O4S: C, 60.96; H, 4.09, N, 9.48; Found: C, 60.58, H, 3.95. N, 9.23.
General procedure for the synthesis of Pyrazole phosphonates (11a-g): To a stirred mixture of 10a (1 mmol), and Bestmann-Ohira Reagent (2.5 mmol) in dry EtOH (10 ml) was added KOH (2.5 mmol) at room temperature, after 2 minutes and irradiated in microwave bath reactor at 500 W for 4–7 minutes at 50°C. The crude product thus obtained was purified by column chromatography on silica gel (60–120 mesh) with hexane-ethyl acetate as eluent. Under conventional method the reaction mixture in EtOH (10 ml) was stirred at room temperature for the appropriate time (Table 2).
Compound | R | Mol. formula | Reaction time | Yield % | ||
---|---|---|---|---|---|---|
A (hours) | B (minutes) | A | B | |||
11a | C6H5 | C33H31ClFN6O6PS | 3.5 | 6 | 62 | 89 |
11b | 4-Cl-C6H4 | C33H30Cl2FN6O6PS | 2.5 | 4 | 60 | 85 |
11c | 4-NO2-C6H4 | C33H30ClFN7O8PS | 2.0 | 5 | 61 | 84 |
11d | 2-CH3-C6H4 | C34H33ClFN6O6PS | 3.0 | 6 | 65 | 86 |
11e | 4-CH3-C6H4 | C34H33ClFN6O6PS | 3.2 | 4 | 69 | 85 |
11f | 3-OH-C6H4 | C35H31ClFN6O7PS | 2.0 | 5 | 72 | 89 |
11g | 4-OH-C6H4 | C35H35ClFN6O7PS | 3.0 | 4 | 71 | 82 |
Synthesis of phosphonyl pyrazoles 11(a–g).
A: conventional method; B: microwave irradiation method.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-phenyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11a): 245–247°C, Yield—75%. 1HNMR (300 MHz, CDCl3): δ13.06 (brs, 1H, 〓NH), 8.03 (s, 1H, Ar-H), 7.70 (d, J = 9.6 Hz, 2H, Ar-H), 7.30 (d, J = 9.2 Hz, 2H, Ar-H), 7.45 (d, J = 8.9 Hz, 2H, Ar-H), 7.19 (d, J = 8.2 Hz, 2H, Ar-H), 6.95–6.70 (m, 5H, Ar-H), 5.80–5.74 (m, 2H, 〓CH), 4.80 (d, J = 5.2 Hz, 1H, CH-S), 4.42 (s, 2H, OCH2), 4.09–3.94 (m, 2H, 2XCH), 3.78 (s, 6H, OCH3), 3.69 (d, J = 6.6 Hz, 2H, OCH2), 3.52 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.1, 160.1, 155.2, 144.1, 141.6, 136.2, 134.1, 129.2, 127.5, 125.6, 122.1, 119.1, 115.8, 86.6, 72.9, 63.8, 53.8, 44.5, 34.9: MS: m/z (M++H) 725. Anal. Calcd for C33H31ClFN6O6PS: C, 54.66; H, 4.31, N, 11.59; Found: C, 54.48, H, 4.05. N, 11.36.
Dimethyl8-(4-chlorophenyl)-7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11b): mp: 206–208°C, Yield—82%. 1HNMR (300 MHz, CDCl3): δ13.11 (brs, 1H, ▬NH), 8.19 (s, 1H, Ar-H), 7.60 (d, J = 9.5 Hz, 2H, Ar-H), 7.54 (d, J = 9.4 Hz, 4H, Ar-H), 7.30 (d, J = 8.6 Hz, 4H, Ar-H), 7.22 (d, J = 8.1 Hz, 2H, Ar-H), 5.80–5.78 (m, 2H, 〓CH), 4.92 (d, J = 5.2 Hz, 1H, CH-S), 4.52 (s, 2H, OCH2), 4.06–3.94 (m, 2H, 2XCH), 3.80 (t, 2H, OCH2), 3.68 (s, 6H, OCH3), 3.54 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.9, 162.1, 155.4, 144.2, 139.8, 134.6, 129.5, 125.8, 124.1, 122.0, 119.2, 115.4, 86.1, 72.5, 64.4, 53.5, 44.8, 34.9: MS: m/z (M++Na) 781. Anal. Calcd for C33H30Cl2 FN6O6PS: C, 52.18; H, 3.98, N, 11.06; Found: C, 51.91, H, 3.65. N, 10.86.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-nitrophenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11c): mp: 231–233°C, Yield—82%. 1HNMR (300 MHz, CDCl3): δ13.06 (brs, 1H, ▬NH), 8.23 (d, J = 8.7 Hz, 2H, Ar-H), 8.06 (s, 1H, Ar-H), 7.65 (d, J = 9.1 Hz, 2H, Ar-H), 7.51 (d, J = 9.4 Hz, 2H, Ar-H), 7.41 (d, J = 8.5 Hz, 2H, Ar-H), 7.10 (d, J = 8.3 Hz, 2H, Ar-H), 6.64 (d, J = 9.8 Hz, 2H, Ar-H), 5.76–5.59 (m, 2H, 〓CH), 4.86 (d, J = 5.2 Hz, 1H, CH-S), 4.35 (s, 2H, OCH2), 4.01–3.93 (m, 2H, 2XCH), 3.72 (s, 6H, OCH3), 3.65 (d, J = 6.9 Hz, 2H, OCH2), 3.45 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ171.1, 162.1, 150.0, 147.8, 144.0, 136.8, 131.4, 128.8, 127.2, 122.0, 119.5, 115.4, 86.4, 72.4, 65.9, 63.9, 53.5, 44.5, 34.8: MS: m/z (M++H) 780. Calcd for C33H30ClFN7O8PS: C, 51.47; H, 3.93, N, 12.73; Found: C, 51.18, H, 3.55. N, 12.49.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-o-tolyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11d): mp: 221–223°C, Yield—75%. 1HNMR (300 MHz, CDCl3): δ13.10 (brs, 1H, ▬NH), 8.02 (s, 1H, Ar-H), 7.59 (d, J = 8.5 Hz, 2H, Ar-H), 7.59 (d, J = 9.2 Hz, 2H, Ar-H), 7.44 (d, J = 8.7 Hz, 2H, Ar-H), 7.42–7.40 (m, 4H, Ar-H), 7.12 (d, J = 9.1 Hz, 2H, Ar-H), 5.76 (m, 2H, 〓CH), 4.92 (d, J = 5.2 Hz, 1H, CHS), 4.62 (s, 2H, OCH2), 4.09–3.99 (m, 2H, CH), 3.74 (s, 6H, OCH3), 3.62 (s, 1H, CH), 3.80 (t, 2H, OCH2), 2.12 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.4, 160.1, 155.1, 144.4, 138.6, 136.2, 134.3, 130.7, 128.6, 127.2, 122.0, 119.2, 116.9, 115.4, 86.1, 72.8, 63.8, 53.5, 44.9, 34.8, 17.9: MS: m/z (M++H) 739. Anal. Calcd for C34H33ClFN6O6S: C, 55.25; H, 4.50, N, 11.37; Found: C, 55.01, H, 4.25. N, 11.09.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-9-oxo-8-p-tolyl-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11e): mp: 209–211°C, Yield—76%. 1HNMR (300 MHz, CDCl3): δ13.01 (brs, 1H, ▬NH), 8.07 (s, 1H, Ar-H), 7.62 (d, J = 9.1 Hz, 2H, Ar-H), 7.50 (d, J = 9.2 Hz, 2H, Ar-H), 7.40 (d, J = 8.7 Hz, 2H, Ar-H), 7.32 (d, J = 8.2 Hz, 2H, Ar-H), 7.18 (d, J = 8.8 Hz, 2H, Ar-H), 6.70 (d, J = 9.4 Hz, 2H, Ar-H), 5.60–5.59 (m, 2H, 〓CH), 4.90 (s, 1H, CHS), 4.45 (s, 2H, OCH2), 4.01–3.99 (m, 2H, CH), 3.94 (t, 2H, OCH2), 3.75 (s, 6H, OCH3), 3.62 (s, 1H, CH), 2.30 (s, 3H, CH3): 13CNMR (75 MHz, CDCl3): δ170.9, 160.1, 155.0, 144.1, 138.7, 136.8, 133.4, 130.4, 129.1, 127.2, 122.0, 119.1, 115.3, 86.1, 72.9, 68.1, 63.9, 53.5, 44.5, 34.8, 21.6: MS: m/z (M++H) 739. Anal. Calcd for C31H26ClFN4O3S: C, 55.25; H, 4.50, N, 11.37; Found: C, 54.98, H, 4.25. N, 11.03.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(3-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11f): mp: 228–229°C, Yield—88%. 1H-NMR (300 MHz, CDCl3): δ13.09 (brs, 1H, ▬NH), 9.40 (brs, 1H, Ph-OH), 8.04 (s, 1H, Ar-H), 7.61 (d, J = 9.7 Hz, 2H, Ar-H), 7.52 (d, J = 9.3 Hz, 2H, Ar-H), 7.42 (d, J = 8.6 Hz, 2H, Ar-H), 7.13 (d, J = 8.4 Hz, 2H, Ar-H), 6.70–6.68 (m, 4H, Ar-H), 5.73–5.70 (m, 2H, =CH), 4.82 (d, J = 5.2 Hz, 1H, CHS), 4.54 (s, 2H, OCH2), 4.14 (t, 2H, OCH2), 4.0–3.97 (m, 2H, CH), 3.70 (s, 6H, OCH3), 3.57 (s, 1H, CH): 13CNMR (75 MHz, CDCl3): δ170.2, 156.1, 155.2, 144.8, 136.8, 129.6, 128.2, 127.5, 122.4, 119.4, 115.4, 106.5, 86.4, 72.5, 66.4, 63.4, 53.5, 44.9, 34.3: MS: m/z (M++H) 741. Anal. Calcd for C33H31ClFN6O7PS: C, 53.48; H, 4.22, N, 11.34; Found: C, 53.18, H, 4.01. N, 11.13.
Dimethyl 7-((2S,3S)-3-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3,6-dihydro-2H-pyran-2-yl)-4-(4-fluorophenyl)-8-(4-hydroxyphenyl)-9-oxo-6-thia-1,2,8-triazaspiro[4.4]non-2-en-3-ylphosphonate (11g): mp: 293–295°C, Yield—69%. 1H-NMR (300 MHz, CDCl3): δ12.85 (brs, 1H, ▬NH), 9.32 (brs, 1H, Ph-OH), 8.02 (s, 1H, Ar-H), 7.65 (d, J = 9.3 Hz, 2H, Ar-H), 7.59 (d, J = 9.2 Hz, 2H, Ar-H), 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 7.30 (d, J = 8.6 Hz, 2H, Ar-H), 7.16 (d, J = 8.3 Hz, 2H, ArH), 7.0 (d, J = 8.8 Hz, 2H, Ar-H), 5.89–5.82 (m, 2H, 〓CH), 4.96 (d, J = 5.4 Hz, 1H, CHS), 4.56 (s, 2H, OCH2), 4.07 (d, J = 2H, OCH2), 4.02–3.99 (m, 2H, CH), 3.82 (s, 6H, OCH3), 3.62 (s, 1H, CH), 13CNMR (75 MHz, CDCl3): δ172.9, 160.5, 154.3, 144.6, 136.2, 134.9, 134.3, 130.4, 129.8, 127.2, 125.6, 123.2, 119.8, 116.1, 86.4, 73.6, 66.5, 64.0, 53.6, 44.8, 34.9: MS: m/z (M++Na) 763. Anal. Calcd for C33H31ClFN6O7PS: C, 53.48; H, 4.22, N, 11.34; Found: C, 53.18, H, 3.99. N, 11.13.
In conclusion, a series of a new class of hybrid heterocyclic’s 11a–g has been synthesized. The nematicidal activity of these compounds was evaluated against Dietylenchus myceliophagus and Caenorhabditis elegans. Among synthesized compounds 11b, 11c, 11f and 11g are the most effective against Dietylenchus myceliophagus and Caenorhabditis elegans the other test compounds showed moderate activity.
The authors are thankful to CSIR-New Delhi for the financial support (Project funding no.: 02 (247)15/EMR-II), Director, CSIR-IICT, Hyderabad, India, for NMR and MS spectral analysis and Principal, Vaagdevi Degree and PG College, Hanamkonda, for his consistent encouragement.
Currently, the fact that considered the leading role of free radical processes in the pathogenesis of more than 200 diseases has been established. Special attention is paid to damage to the brain tissue due to their particular sensitivity to disruption of oxygen balance and redox balance. The chain character of the reactions of lipid peroxidation (LPO) causes the appearance of a whole cascade of reactive oxygen forms, including superoxide, hydroxyl, and perhydroxyl radicals, singlet oxygen, hydrogen peroxide, and their active metabolites (nitrogen oxide, hypochlorite, etc.). The result is a violation of the integrity and permeability of the cell membrane and the destruction of proteins, lipids, carbohydrates, and nucleic acids, the cell genome suffers, and degenerative changes and neuron death develop. The processes of lipid peroxidation underlie most of the diseases of the central nervous system, which include acute and chronic disorders of cerebral blood circulation, degenerative diseases of the brain and spinal cord, cancer pathology, etc. [1, 2].
Antioxidants, both endogenous and exogenous substances, limit LPO processes. Today, in practical health care, antioxidant preparations of natural origin and synthetic compounds are used [3]. It should be noted that the group of drugs related to natural antioxidants has found quite wide application in clinical practice. At the same time, there is a clear shortage of synthetic antioxidant drugs. In view of the abovementioned, the emergence of a new effective antioxidant compound should arouse the interest of qualified specialists.
A computer prediction of the antioxidant activity of new compounds was carried out in the “Microcosm” software [4], and the high predictive ability of the “Microcosm” information technology regarding the antioxidant activity of imidazo-benzimidazole derivatives has been demonstrated.
Condensed benzimidazole derivatives were synthesized, and experimental screening of the antioxidant activity of new chemical compounds was carried out among the derivatives of 2-(hetaryl) imidazo[1,2-a]benzimidazoles (IMBI) [5], 3-aroyl- and 3-hetaroyl-IMBI [6], 2-methoxyphenyl-substituted 9-dialkylaminoethyl-IMBI [7], 2-methoxy- phenyl- and 2-oxyphenyl-substituted 1-dialkylaminoalkyl-IMBI [8], N-acylmethyl derivatives of 9H-2,3-dihydro-IMBI and 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles [9], 9-dialkylaminoethyl-2-oxy(dioxy)phenyl-IMBI [10], aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals [11], 3-(2,2,2-trichloro-1-hydroxyethyl)-IMBI [12], 3-acetyl-2-R-9-dialkylaminoethyl-IMBI [13], 1-dialkyl(alkyl)aminoethyl-2,3-dihydro-IMBI [14], 9-R-2-halogenophenyl-IMBI [15], 10-alkylaminoethyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles [16], 3-(n,n-disubstituted)acetamide-1-r-2-aminobenzimidazolium [17], amides of 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazolyl-acetic acids [18], phenyl- and alkylthiocarbamides of 2,9-disubstituted IMBI [19], and 1-substituted 2-benzylaminobenzimidazoles with phenyl methoxyls [20]. Butylated hydroxytoluene (BHT, CAS Number 128-37-0), also known as dibunol, was chosen as a comparative drug.
It was found that among the derivatives of 2-(hetaryl)-IMBI, high antioxidant activity superior to dibunol was shown by compounds containing in the second position of the tricycle such substituents as 1-methylbenzimidazolyl and 5-bromothienyl. The remaining substances of this series showed an average level of activity, similar to or inferior to dibunol [5]. Among the 3-aroyl- and 3-hetaroyl-IMBI, no substances with antioxidant activity were found [6]. Among 2-methoxyphenyl-substituted 9-dialkylaminoethyl-IMBI, 4-methoxy- and 3 methoxyphenyl-IMBI showed the greatest antioxidant effect, which was comparable to or exceeded dibunol [7]. Salts of the compounds 9-dialkylaminoethyl-IMBI with 3,4-dioxyphenyl substitute exhibited the greatest antioxidant activity that was twofold active than reference drug BHT. Compounds with 4- and 3-oxyphenyl substitutes or 2,4- and 2,5-dioxyphenyl substitutes, as a rule, laсked 3,4-dioxyphenyl-IMBI in activity; however they were similar in it to BHT [10]. Most of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals also proved to be highly active antioxidant substances that were superior to dibunol [11]. Derivatives of 9-R-2-halogenophenyl-IMBI had a pronounced inhibitory effect on the processes of lipid peroxidation comparable to dibunol [15]. The compounds from the series of 1-substituted 2-benzylaminobenzimidazoles with phenyl methoxyls acted similarly [20]. Amides of 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazolyl-acetic acids showed moderate AO activity compared to dibunol [18]. It was revealed that 2-methoxy-phenyl- and 2-oxyphenyl-substituted 1-dialkylaminoalkyl-IMBI [8], N-acylmethyl derivatives of 9H-2,3-dihydro-IMBI and 10H-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles [9], most of 3-(2,2,2-trichloro-1-hydroxyethyl)-IMBI [12] и 3-acetyl-2-R-9-dialkylaminoethyl-IMBI [13], 1-dialkyl(alkyl)aminoethyl-2,3-dihydro-IMBI [14], and 3-(n,n-disubstituted)acetamide-1-r-2-aminobenzimidazolium [17] showed the weak antioxidant activity compared to the reference drug. Among 10-alkylaminoethyl-2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles [16] and phenyl- and alkylthiocarbamides of 2,9-disubstituted IMBI [19], antioxidant action has not been found.
As a result of previous investigations, the 2-(3,4-dihydroxyphenyl)-9-diethylaminoethyl-imidazo [1,2-a]benzimidazole derivative of dihydrobromide (RU-185, enoxifol) was identified as an antioxidant compound with antiradical and membrane-protective properties [21, 22], having multicomponent mechanisms of action and a wide range of pharmacodynamic effects. For enoxifol, a cardioprotective effect and a positive effect on the microcirculation of blood vessels are characteristic. Antioxidant compound reduces platelet aggregation [23, 24, 25], reduces increased blood viscosity, and increases red blood cell deformability [26]. Preclinical toxicology studies have been carried out, and the pharmacokinetics of the compound has been studied [27].
Synthesis of 2-(3,4-dihydroxyphenyl)-9-diethylamino-ethylimidazo[1,2-a]benzimidazole dihydrobromide (RU-185) starts from saponification of benzimidazole-2-carbamic acid methyl ester under alkaline conditions to obtain 2-aminobenzimidazole. Subsequent alkylation in acetone in the presence of alkali with N,N-diethylaminoethyl chloride formed by the action of thionyl chloride on N,N-diethylaminoethanol and condensation with a 3,4-dimetoxiphenacylbromide or or 3,4-dioxiphenacyl chloride, followed by intermolecular cyclization in 48% hydrobromic acid (boiling temperature 127°C) under reflux, afforded target compound RU-185.
2-Aminobenzimidazole is obtained by saponification of benzimidazole-2-carbamic acid methyl ester (BMС-2) in aqueous solution of sodium hydroxide. The yield of 2-aminobenzimidazole is 65–75%. At the next stage, 2-aminobenzimidazole is used with a melting point of 223–232°С (within 2 degrees). If necessary, the amine is purified by crystallization from water and acetone or by precipitation from an aqueous hydrochloric acid solution.
Diethylaminoethyl chloride hydrochloride is obtained by chlorination of diethylaminoethanol with thionyl chloride in toluene or benzene. Purification can be performed by distillation at atmospheric pressure, collecting the fraction with 161–162°C boiling point.
Diethylaminoethanol was distilled in case of poor quality and dried over anhydrous potassium carbonate (1:10 w/v) prior to use. After standing for 6–8 hours with periodic stirring, the desiccant was filtered off. Thionyl chloride (technical) was also distilled at atmospheric pressure before use (boiling point 74–75°C).
2-Amino-1-diethylaminoethylbenzimidazole is obtained by alkylation of 2-aminobenzimidazole with N,N-diethylaminoethyl chloride in acetone in a presence of a concentrated alkali solution. Upon completion of the reaction, the acetone is distilled off at atmospheric pressure and can be used at the same stage without further purification. Water is added to the residue, and the precipitate of the alkylated amine is filtered off to give 82–88% yield.
Synthesis of compound RU-185 is achieved by treatment of 2-amino-1-diethylaminoethylbenzimidazole with α-chloro-3,4-dihydroxyacetophenone [28] (Method A) or with 3,4-dimethoxyphenacyl bromide. Subsequent cyclization of the formed quaternary 2-aminobenzimidazole salts is achieved in concentrated HBr (Method B).
Method A The method consists of boiling of 1-diethylaminoethyl-2-aminobenzimidazole and α-chloroacetopyrocatechol in dry acetonitrile until the quaternization reaction is complete (2–3 hours with TLC control). Then the solvent is evaporated to dryness, and concentrated HBr is added followed by reflux for 1–2 hours. Reaction mixture is left overnight in the refrigerator. The next day, the precipitate formed (large needles) is filtered off. The yield of dihydrobromide (I) is 97%. Recrystallization of the crude product from 80% aqueous ethanol with addition of activated charcoal affords white crystals with a yield of 85%. The product should be protected from direct sunlight. After drying at 110–120°C, the melting point of dihydrobromide is 289–290°C (decomposition).
Method B 3,4-Dimethoxyphenacyl bromide is added to a hot solution of 2-amino-1-diethylaminoethylbenzimidazole in acetone (molar ratio 1:1). Next, the mixture is kept for 6–8 hours at room temperature. The precipitate of 2-amino-(3,4-dimethoxyphenacyl)-1-diethylaminoethylbenzimidazolium bromide is filtered off. The output is 93.5% and melting point 182°C (decomposition, from ethanol).
Next, the resulting bromide is refluxed in conc. HBr (127°C) for 6–8 hours, while as the boiling of the initially formed solution precipitates. After cooling, it is filtered off, washed with acetone, and air dried. The yield is 96%. Crystallization from 80% aqueous ethanol gives (3,4-dihydroxyphenyl)-9-diethylaminoethyl-imidazo[1,2-a]benzimidazole dihydrobromide (I) identical to the product described in method A.
For several years, the ability of compounds to inhibit oxidative processes in the cells of various tissues, organs, and biological fluids has been thoroughly investigated. The study of the antioxidant properties of enoxifol was carried out by several methods: ascorbate-induced LPO according to the method [29], Fe2+-induced chemiluminescence (CL) of lipids [30], and NADPH-dependent LPO [31]. Superoxide dismutase-like activity has been studied in a quercetin oxidation model [32], interaction with the free radical of 2,2-diphenyl-1-picrylhydrazyl (DPPH*) according to the method [33], and interaction with reactive oxygen species on the luminol-dependent CL model [34], the ability to inactivate the superoxide anion radical was estimated by the xanthine-xanthine oxidase-induced lucigenin-dependent CL method [2], and the ability of substances to intercept and inactivate the peroxyl radical was determined by the ABAP-induced CL method [35]. The spectrum of antioxidant activity of enoxifol and the reference compound trolox is shown on Figure 1. It was found that enoxifol can react with lipid peroxyl radicals at the chain termination stage, as indirectly evidenced by its high inhibitory activity during ascorbate, NADPH-induced lipid peroxidation, and CL of lipids, as well as directly inactivate superoxide, hydroxyl, and peroxyl radicals that initiate oxidation, as demonstrated in reactions with the free radical DPPH, quercetin oxidation, Fe2+-induced CL in the presence of luminol, xanthine-xanthine oxidase induced by lucigenin-dependent CL, as well as thermal decomposition of the water-soluble compound 2,2-azobis (2-methylpropionamidine) dihydrochloride (ABAP) with the release of peroxyl radicals, inactivating free radicals and enoxifol, thereby reducing the overall oxidation rate by reducing the total initiation rate [35, 36].
Antioxidant activity spectrum of enoxifol (A) and trolox (B) (−Lg IC50 (М)).
As a result of the analysis of the chemical structure of enoxifol, the structural descriptors were determined, allowing the compound to exhibit antioxidant and antiradical activities. The molecule of enoxifol can manifest these properties due to a fragment of 3,4-dihydroxyphenyl and π-electronic redundancy of the imidazole ring in the structure of imidazobenzimidazoles [37]. Given the relatively low toxicity and high antioxidant potential, the compound was selected for in-depth study on pathological models.
Membranoprotective activity of enoxifol was studied using the model [38], determining the mechanical strength and resistance of erythrocyte membranes to the hypoosmotic HCl solution. The membrane-stabilizing activity of the compound (inhibition of slow and fast incoming transmembrane ion currents) has been revealed. An effective dose of a compound of 20.5 mg/kg has been established [39].
When studying the hepatoprotective properties of enoxifol with a 3-day prophylactic administration in dose 2.25 mg/kg on a model of acute tetrachloromethane hepatitis, it was found that enoxifol significantly improved the absorption and excretory function of the liver and its detoxification abilities Under its influence the development of signs of the cytolytic, hepatodepressive, mesenchymal-inflammatory, and cholestatic syndrome was significantly inhibited, surpassing tocopherol acetate in effectiveness [40].
The antihypoxic properties of enoxifol have been studied in several models of hypobaric, hemic, and tissue hypoxia. In particular, the activity of the compound was established during intrauterine hypoxia and during recovery after acute hypobaric hypoxia. The potential protective effect of the antioxidant compound in hypobaric hypoxia was determined in high- and low-resistant to hypoxia animals in a flow-type pressure chamber at the “height” of 12,500 and 11,000 m, respectively [41]. The most effective doses in these models were 3 and 5 mg/kg [42]. Enoxifol showed a protective effect in modeling intrauterine hypoxia in dose 10 mg/kg during course administration [42].
The activity of the compound in the recovery period after acute hypobaric hypoxia was determined by the change in behavioral reactions, cognitive functions, and the physical condition of the animals. The protective dose of enoxifol was 5 mg/kg. Tissue and hemic hypoxias were created by injecting potassium cyanide and sodium nitrite, respectively [43]. The protective action of enoxifol was judged by the degree of survival of the animals. The range of effective doses was determined from 0.5 to 5 mg/kg [44].
The cerebroprotective effect of enoxifol was established on two models of cerebral ischemia of two and four vascular ligature of the carotid and paravertebral arteries, respectively, as well as during the reperfusion period [25, 44]. Antioxidant compound significantly increased the survival rate of animals, decreased blood viscosity by reducing platelet and red blood cell (RBC) aggregation and improving the mechanical properties of RBC, and corrected the behavioral deficit in the postischemic period. Doses of enoxifol in which the cerebroprotective activity was established were 5 and 10 mg/kg.
Nootropic activity of enoxifol was established in the model of the conditioned passive avoidance reaction, which allows to evaluate the effect of a studied compounds on learning and memory. As a result, it was found that enoxifol influenced the ability of animals to consolidate information, reduced the deficit in the reproduction of a memorable trace, and intensified the input and initial processing of information in dose 10 mg/kg. The study of the enoxifol effect on the research behavior and emotionality of animals was carried out in the open-field modified test that allows to evaluate the nonassociative behavior of animals in familiar surroundings. Against the background of a 3-day course of administration of the antioxidant compound in dose of 10 mg/kg, psycho-emotional reactivity and anxiety in animals were decreased. With repeated testing, the memories of the arena research were better preserved. Experiments conducted in a Morris maze test confirmed the potential ability of enoxifol in a similar dose to increase mnestic abilities and improve the spatial orientation of animals [45].
The stress-protective effect of enoxifol was studied on models of short-term (1 hour) and prolonged (48 hours) hypokinetic stress [46] and hyperkinetic stress with the paradoxical sleep phase deprivation in rats, in the test of slowly rotating rod [47]. Enoxifol was administered to animals in doses 5 and 10 mg/kg. An antioxidant compound showed an ambiguous therapeutic effect depending on the experimental model used. The antioxidant was not effective in the short-term hypokinetic stress technique. Enoxifol reduced post-stress injuries of internal organs and corrected the targeted behavior of animals in prolonged hypokinetic stress. Enoxifol did not affect the behavioral activity of rats but protected internal organs from pathological abnormalities in hyperkinetic stress [37].
The effect of enoxifol on physical performance and recovery period after physical exertion was studied under normal and complicated conditions in several experimental models. We used the swim to the limit test [48], fatigue development test [49], and efficiency test in anti-orthostatic condition [50]; the model allows to study the recovery process after exercises [51] and the method of research of animals’ endurance to training and exhausting loads [49]. Actoprotective properties were studied in models associated with limiting physical loads (swimming to failure), with the rate of fatigue development, and in the test of swimming in complicated anti-orthostatic condition. Enoxifol increased the duration of physical performance under normal and complicated conditions, stabilized some indicators of energy metabolism (the level of lactate, glycogen, tryptophan, the ratio of pyruvate and lactate), normalized indicators of lipid peroxidation, and had a protective effect on the myocardium of animals during the period of exhaustive physical activity. A number of effective doses amounted to 1, 3, 5, 10, 20, 25, and 50 mg/kg in various physical activity tests [52].
Cardioprotective activity was studied in isolated atrial rhythm disturbances induced by hydrogen peroxide oxidation [53], in postischemic reperfusion fibrillations of the heart ventricles [54], in the technique of rhythm disturbances caused by calcium chloride and adrenaline intoxication [55], and in the myocardial ischemia provoked by coronary occlusion [31] and the experimental myocardial infarction method [56]. As a result it was found that enoxifol exerted an antiarrhythmic effect, increasing the resistance of cardiomyocyte membranes to LPO products. The compound increased the stability of the myocardium of animals having a non-antioxidant diet to calcium chloride cardiac arrhythmias and increased myocardial tolerance to ischemia. Enoxifol completely prevented ventricular fibrillation of the heart in postischemic myocardial reperfusion. It reduced the extrasystole severity and ventricular fibrillation and reduced the death of animals in the model of coronary artery occlusion and systemic peroxidation syndrome. The novel compound limited area of necrosis in experimental myocardial infarction. It showed activity in doses 7.9, 14, and 20.5 mg/kg [39, 55].
Enoxifol had a pronounced antithrombotic effect in arterial thrombosis models induced by application of ferric chloride and electric current on the rat carotid artery and blocked platelet aggregation caused by ADP, collagen, adrenaline, arachidonic acid, thrombin, and an agonist of thromboxane receptors U46619 [24]. The antioxidant compound reduced levels of proaggregant and vasoconstrictor ТХА2, which was confirmed by a decreased level of MDA in the ex vivo pathology caused by thrombin, and decreased the level of total and membrane-bound calcium in platelets, inhibiting calmodulin-dependent PDE cAMP.
The study of the enoxifol action on hemorheology was carried out in the model of “increased viscosity syndrome” according to the method [57]. An improvement in blood flow, membrane plasticity, and inhibition of erythrocyte aggregation under the influence of enoxifol administration in dose 5 mg/kg was found [18]. An increase in the rate of local cerebral blood flow and a direct effect on the tone of cerebral vessels in a similar dose were determined in the method of tissue microcirculation [58]. The study of the enoxifol effect on hemorheology in models of severe forms of streptozotocin diabetes was also performed. Antioxidant compound corrected hemobiological parameters (aggregation, deformability, mechanical properties of erythrocytes), almost normalized indicators of lipid peroxidation, reducing the products of peroxidation, and increased the activity of antioxidant enzymes. The effective dose was 5 mg/kg for the course of the 3-day administration preliminary to diabetes modeling [58].
In the study of the pharmacokinetic properties of enoxifol [27], determination was carried out for 12 hours in the blood and internal organs and in the urine and feces within 48 hours. It was found that the absolute bioavailability of unchanged enoxifol was 30% and for the total amount of enoxifol and its active metabolites, 99%. When administered orally, enoxifol was well absorbed from the gastrointestinal tract, the maximum concentration in the blood was observed after 1 hour, and after 7 hours the compound was not detected. The excretion of the compound occurs mainly through the intestines, and only one-fifth is excreted unchanged; a small amount of enoxifol is excreted through the kidneys. The half-life for enoxifol was 1.43 hours. After the intravenous administration, the maximum concentration of the compound in the blood is determined in 10 minutes; after 7 hours the antioxidant in the blood was not recorded. The excretion of the infusion form of enoxifol occurs mainly through the kidneys in the unchanged form. In a much smaller amount, enoxifol was eliminated with feces. The half-life was 0.78 hours [27].
A study of the drug safety of enoxifol [59] found that the antioxidant compound can be attributed to low-toxic substances. The acute toxicity of enoxifol after oral administration was 1792.56 mg/kg for male and 2260.28 mg/kg for female rats. When administered intravenously, the LD50 was determined for male in dose 109.20 mg/kg and for female rats in dose 126.04 mg/kg. Chronic administration in therapeutic doses (5–25 mg/kg) showed that toxic effects in the central nervous system, liver function, kidney function, and the generative system were not observed. In the high dose (200 mg/kg), slight deviations in the behavioral responses of animals and a slight decrease in the detoxification function of the liver were observed. The accumulation ability of enoxifol wasn’t found [59].
Summarizing the data obtained, we can conclude that condensed benzimidazole derivatives with π-electron redundancy are a new scaffold for searching antioxidant substances. The highest amount of compounds with high antioxidant activity was found in derivatives of 2-(hetaryl)-aroylmethyl-, and 9-dialkylaminoethyl-IMBI, with oxy- and dioxyphenyl substitutes especially.
The revealed compound enoxifol from the 9-dialkylaminoethyl-IMBI series exhibits pronounced antioxidant, hepatoprotective, antihypoxic, cerebroprotective, nootropic, stress-protective, neuropsychotropic, actoprotective, cardioprotective, antithrombogenic and hemorheological properties. Pharmacokinetic parameters of enoxifol were established, and general and specific toxicities were studied. All mentioned above allows us to consider enoxifol to be the basis of a new effective drug.
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