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Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE


Rivastigmine has been prescribed for the therapy of Alzheimer’s disease (AD) symptoms. This drug is classified in the carbamate derivative group that has dual activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). According to the structure of Rivastigmine and its performance, a new series of 5-aryl-1,3,4-oxadiazole-2-carbamothioate compounds I–XI was synthesized using structure-based drug discovery approaches. For this purpose a set of these compounds were designed with computational docking method and their interactions with amino acid residues in the active sites of AChE and BuChE checked out. The structures of synthesized compounds were established by physicochemical and spectroscopic methods. The carbamoyl moiety of Rivastigmine structure was modified to carbamothioate and the effects of 1,3,4-oxadiazole heterocycle as a pharmacophoric nucleus were investigated. The potential of the synthesized compounds I–XI was evaluated against two most known agents of AD (AChE and BuChE) to determine their IC50 values. The results of the docking showed the range of binding affinity for the best poses of ten individual conformers for any compounds (I–XI) was between −7.81 (VI) and −6.75 (II) kcal/mol. The results of biological experiments displayed that most synthetic compounds (I–VIII) showed moderate to excellent selective activity range against BuChE (0.51–69.44 µM). In vitro cytotoxicity evaluation of these compounds (I–XI) by MTT assay on human dermal fibroblast (HDF) cell line exhibited no activity against HDF. The compound VI [S-(5-(p-tolyl)-1,3,4-oxadiazol-2-yl) ethyl(methyl)carbamothioate] showed the most stable binding affinity (−7.81 kcal/mol) and the lowest IC50 value (0.51 µM) in comparison with Rivastigmine with 7.72 µM and Donepezil with 5.20 µM against BuChE.

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  1. Abolhasani MH, Safavi M, Goodarzi MT, Kassaee SM, Azin M (2018) Identification and anti-cancer activity in 2D and 3D cell culture evaluation of an Iranian isolated marine microalgae Picochlorum sp. RCC486. Daru J Pharm Sci 26:105–116

  2. Bajda M, Łatka K, Hebda M, Jonczyk J, Malawska B (2018) Novel carbamate derivatives as selective butyrylcholinesterase inhibitors. Bioorg Chem 78:29–38

  3. Bingul M, Saglam MF, Kandemir H, Boga M, Sengul IF (2019) Synthesis of indole-2-carbohydrazides and 2-(indol-2-yl)-1,3,4-oxadiazoles as antioxidants and their acetylcholinesterase inhibition properties. Monatsh Chem

  4. Boström J, Hogner A, Llinas A, Wellner E, Plowright AT (2012) Oxadiazoles in medicinal chemistry. J Med Chem 55:1817–1830

  5. Danish M, Raza MA, Anwar U, Rashid U, Ahmed Z (2019) Differential functional theory and molecular docking studies of newly synthesized carbamates. J Chin Chem Soc

  6. Faraji L, Nadri H, Moradi A, Bukhari SN, Pakseresht B, Moghadam FH, Moghimi S, Abdollahi M, Khoobi M, Foroumadi A (2019) Aminoalkyl-substituted flavonoids: synthesis, cholinesterase inhibition, β-amyloid aggregation, and neuroprotective study. Med Chem Res 28:974–983

  7. Ghobadian R, Esfandyari R, Nadri H, Moradi A, Mahdavi M, Akbarzadeh T, Khaleghzadeh-Ahangar H, Edraki N, Sharifzadeh M, Amini M (2019) Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors. Mol Divers

  8. Gudi Y, Mangali MS, Gundala S, Venkatapuram P, Adivireddy P (2018) Synthesis, characterization, and bioassay of a new class of pyrazolyl/isoxazolyl oxadiazoles. Monatsh Chem 149:2311–2326

  9. Hariri R, Afshar Z, Mahdavi M, Safavi M, Saeedi M, Najafi Z, Sabourian R, Karimpour-Razkenari E, Edraki N, Moghadam FH, Shafiee A, Khanavi M, Akbarzadeh T (2016) Novel tacrine-based pyrano[3’,4’:5,6]pyrano[2,3-b]quinolinones: synthesis and cholinesterase inhibitory activity. Arch Pharm Chem Life Sci 349:1–10

  10. Kang L, Gao XH, Liu HR, Men X, Wu HN, Cui PW, Oldfield E, Yan JY (2018) Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors. Mol Divers 22:896–906

  11. Karabanovich G, Zemanová J, Smutný T, Székely R, Šarkan M, Centárová I, Vocat A, Pávková I, Čonka P, Němeček J, Stolaříková J, Vejsová M, Vávrová K, Klimešová V, Hrabálek A, Pávek P, Cole ST, Mikušová K, Roh J (2016) Development of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and thiadiazoles as selective antitubercular agents active against replicating and nonreplicating mycobacterium tuberculosis. J Med Chem 59:2362–2380

  12. Koola MM, Praharaj SK, Pillai A (2019) Galantamine-memantine combination as an antioxidant treatment for schizophrenia. Curr Behav Neurosci Rep. 6:37–50

  13. Li P, Shi L, Gao MN, Yang X, Xue W, Jin LH, Hu DY, Song BA (2015) Antibacterial activities against rice bacterial leaf blight and tomato bacterial wilt of 2-mercapto-5-substituted-1,3,4-oxadiazole/thiadiazole derivatives. Bioorg Med Chem Lett 25:481–484

  14. Mahajan PG, Dige NC, Vanjare BD, Raza H, Hassan M, Seo SY, Kim CH, Lee KH (2019) Synthesis and biological evaluation of 1,2,4-triazolidine-3-thiones as potent acetylcholinesterase inhibitors: in vitro and in silico analysis through kinetics, chemoinformatics and computational approaches. Mol Divers

  15. Makhaeva GF, Kovaleva VN, Lushchekina SV, Rudakova EV, Boltneva NP, Proshin AN, Lednev BV, Serkov IV, Bachurin SO (2018) Conjugates of Tacrine and its cyclic homologues with p toluenesulfonamide as novel acetylcholinesterase and butyrylcholinesterase inhibitors. Dokl Biochem Biophys 483:369–373

  16. Mohammadi-Khanaposhtani M, Mahdavi M, Saeedi M, Sabourian R, Safavi M, Khanavi M, Foroumadi A, Shafiee A, Akbarzadeh T (2015) Design, synthesis, biological evaluation, and docking study of acetylcholinesterase inhibitors: new acridone-1,2,4-oxadiazole-1,2,3-triazole hybrids. Chem Biol Drug Des 86:1425–1432

  17. Morán-Díaz JR, Jiménez-Vázquez HA, Gómez-Pliego R, Arellano-Mendoza MG, Quintana-Zavala D, Guevara-Salazar JA (2019) Correlation study of antibacterial activity and spectrum of Penicillins through a structure-activity relationship analysis. Med Chem Res 28:1529–1546

  18. Najafi Z, Mahdavi M, Saeedi M, Sabouriane R, Khanavi M, Safavi M, Tehrani MB, Shafieeh A, Foroumadih A, Akbarzadeh T (2016) 1,2,3-Triazole-Isoxazole based acetylcholinesterase inhibitors: synthesis, biological evaluation and docking study. Lett Drug Des Disco 14:58–65

  19. Nayak SG, Poojary B (2019) A review on the preparation of 1,3,4-oxadiazoles from the dehydration of hydrazines and study of their biological roles. Chem Afr

  20. Nunes N, Rosa GP, Ferraz1 S, Barreto MC, Carvalho MP (2019) Fatty acid composition, TLC screening, ATR-FTIR analysis, anti-cholinesterase activity, and in vitro cytotoxicity to A549 tumor cell line of extracts of 3 macroalgae collected in Madeira. J Appl Phycol

  21. Özdemir Z, Yılmaz H, Sar S, Karakurt A, Şeno FS, Uysa M (2017) Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors. Med Chem Res 26:2293–2308

  22. Pordeli M, Nakhjiri M, Safavi M, Ardestani SK, Foroumadi A (2017) Anticancer effects of synthetic hexahydrobenzo [g]chromen-4-one derivatives on human breast cancer cell lines. Breast Cancer 24:299–311

  23. Purgatorio R, Candia MD, Catto M, Carrieri A, Pisani L, Palma AD, Toma M, Ivanova OA, Voskressensky LG, Altomare CD (2019) Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease. Eur J Med Chem 177:414–424

  24. Rohand T, Ramli Y, Baruah M, Budka J, Das AM (2019) Synthesis, structure elucidation and antimicrobial properties of new bis-1,3,4-oxadiazole derivatives. Pharm Chem J 53:150–154

  25. Roy PP, Banjare P, Verma S, Singh J (2019) Acute rat and mouse oral toxicity determination of anticholinesterase inhibitor carbamate pesticides: a QSTR approach. Mol Inform 38:1800151–1800167

  26. Saeed A, Shah MS, Larik FA, Khan SU, Channar PA, Flörke U, Iqbal J (2017) Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors. Med Chem Res 26:1635–1646

  27. Saeedi M, Safavi M, Karimpour-Razkenari E, Mahdavi M, Edraki N, Moghadam FH, Khanavi M, Akbarzadeh T (2017) Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease. Bioorg Chem 70:86–93

  28. San Juan AA, Bacalhau P, Goth A, Caldeira AT, Martins R, Burke AJ (2016) Insights into (S)-Rivastigmine inhibition of butyrylcholinesterase (BuChE): molecular docking and saturation transfer difference NMR (STD-NMR). Bioorg Chem 67:105–109

  29. Sekhar MM, Yamini G, Divya KR, Padmavathi V, Padmaja A (2019) Synthesis and bioassay of a new class of disubstituted 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles. Med Chem Res 28:1049–1062

  30. Shamsimeymandi R, Pourshojaei Y, Eskandari K, Mohammadi-Khanaposhtani M, Abiri A, Khodadadi A, Langarizadeh A, Sharififar F, Amirheidari B, Akbarzadeh T, Lotfian H, Foroumadi A, Asadipour A (2019) Design, synthesis, biological evaluation, and molecular dynamics of novel cholinesterase inhibitors as anti-Alzheimer's agents. Arch Pharm Chem Life Sci 352:1800352–1800363

  31. Shi DH, Ma XD, Liu YW, Min W, Yin FJ, Tang ZM, Song MQ, Lu C, Song XK, Liu WW, Dong T (2018) Synthesis, crystal structure and biological evaluation of novel 2-phenylthiazole derivatives as butyrylcholinesterase inhibitors. J Chem Res 42:366–370

  32. Shingare RM, Patil YS, Sangshetti JN, Patil RB, Rajani DP, Madje BR (2018) Synthesis, biological evaluation and docking study of some novel isoxazole clubbed 1,3,4-oxadiazoles derivatives. Med Chem Res 27:1283–1291

  33. Simurova NV, Maiboroda OI (2019) Synthesis of mono- and disubstituted 1,3,4-oxadiazoles (microreview). Chem Heterocycl Compd 55:604–606

  34. Turkan F, Cetin A, Taslimi P, Karaman HS, Gulçin İ (2019) Synthesis, characterization, molecular docking and biological activities of novel pyrazoline derivatives. Arch Pharm Chem Life Sci 352:1800359–1800370

  35. Yadav E, Singh D, Debnath B, Rathee P, Yadav P, Verma A (2019) Molecular docking and cognitive impairment attenuating efect of phenolic compound rich fraction of Trianthema portulacastrum in scopolamine induced Alzheimer’s disease like condition. Neurochem Res 44:1665–1677

  36. Yan L, Deng M, Chen A, Li Y, Zhang W, Du ZY, Dong CZ, Meunier B, Chen H (2019) Synthesis of N-pyrimidin[1,3,4]oxadiazoles and N-pyrimidin[1,3,4]-thiadiazoles from 1,3,4-oxadiazol-2-amines and 1,3,4-thiadiazol-2-amines via Pd-catalyzed heteroarylamination. Tetrahedron Lett 60:1359–1362

  37. Yazdani M, Edraki N, Badri R, Khoshneviszadeh M, Iraji A, Firuzi O (2019) 5,6-Diphenyl triazine-thio methyl triazole hybrid as a new Alzheimer’s disease modifying agents. Mol Divers

  38. Yusufzai SK, Khan MS, Sulaiman O, Osman H, Lamjin DN (2018) Molecular docking studies of coumarin hybrids as potential acetylcholinesterase, butyrylcholinesterase, monoamine oxidase A/B and β-amyloid inhibitors for Alzheimer’s disease. Chem Cent J 12:128–185

  39. Zengin M, Unsal-Tan O, Küçükkýlýnç TT, Ayazgok B, Balkan A (2019) Design and synthesis of 2-substituted phenyl benzo[d]thiazole derivatives and their b-amyloid aggregation and cholinesterase inhibitory activities. Pharm Chem J 53:322–328

  40. Zhang XZ, Xu Y, Jian MM, Yang K, Ma ZY (2019) Synthesis, in vitro assays, molecular docking, theoretical ADMET prediction, and evaluation of 4 methoxy-phenylthiazole-2-amine derivatives as acetylcholinesterase inhibitors. Med Chem Res 28:1683–1693

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The authors are thankful to Department of Chemical Technologies, Iranian Research Organization for Science and Technology (IROST) for financial support of this study.

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Correspondence to Maliheh Safavi.

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Fallah, A., Mohanazadeh, F. & Safavi, M. Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE. Med Chem Res 29, 341–355 (2020).

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  • 1,3,4-oxadiazole
  • Carbamothioate
  • Rivastigmine
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Selective inhibitor