Synthesis, in silico studies and cytotoxicity evaluation of novel 1,3,4-oxadiazole derivatives designed as potential mPGES-1 inhibitors

Abstract

A series of new 1,3,4-oxadizole derivatives containing thioether group, has been synthesized to investigate their mPGES-1 inhibitory activities. The synthesized compounds were also evaluated for their anticancer and COX-1/2 inhibitory activities. All compounds were checked for their purity using TLC and HPLC analyses. The melting points, elemental analysis, FT-IR, 1H-/13C-NMR and LR-MS data were utilized for structural characterization. The most potent derivative was 2-[5-{[2-methyl-5-(propan-2-yl)phenoxy]methyl}-1,3,4-oxadiazol-2-yl)sulphanyl]-1- (phenyl)ethan-1-one 3a, which showed inhibitory activity against mPGES-1 with an IC50 of 4.95 μM. Docking studies with mPGES-1 and COX-1/2 enzymes revealed their affinity and potential binding mechanism for the tested compounds.

Keywords

• 1,3,4-Oxadiazoles
• thioethers
• mPGES-1 inhibition
• COX-1/2 inhibition
• anticancer activity
• molecular docking
• ADME prediction

References

1. [1] Basile L, Álvarez S, Blanco A, Santagati A, Granata G, Di Pietro P, Guccione S, Muñoz-Fernández MA. Sulfonilamidothiopyrimidone and thiopyrimidone derivatives as selective COX-2 inhibitors: Synthesis, biological evaluation and docking studies. Eur J Med Chem. 2012; 57(0): 149-161. [CrossRef]
2. [2] Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur J Med Chem. 2003; 38(7–8): 645-659. [CrossRef]
3. [3] Dannhardt G, Kiefer W. Cyclooxygenase Inhıbitors-Current Status and Future Prospects. Eur J Med Chem. 2001; 36: 109-126. [CrossRef]
4. [4] Samuelsson B, Morgenstern R, Jakobsson PJ. Membrane prostaglandin E synthase-1: A novel therapeutic target. Pharmacol Rev. 2007; 59: 207-224. [CrossRef]
5. [5] Akasaka H, So SP, Ruan KH. Relationship of the topological distances and activities between mPGES-1 and COX-2 versus COX-1: implications of the diffirent post- translational endoplasmic reticulum organizations of COX-1 and COX-2. Biochemistry. 2015; 54: 3707-3715. [CrossRef]
6. [6] Whittle BJR. Gastrointestinal effects of nonsteroidal anti‐inflammatory drugs. Fund Clin Pharmacol. 2003; 17(3): 301- 313. [CrossRef]
7. [7] Laine L. The gastrointestinal effects of nonselective NSAIDs and COX-2 selective inhibitors. Semin Arthritis Rheum. 2002; 32(3): 25-32. [CrossRef]
8. [8] Chang HH, Meuillet EJ. Identification and development of mPGES-1 inhibitors: where are we at? Future Med Chem. 2011; 3(15): 1909-1934. [CrossRef]

9. [9] Bülbül B, Küçükgüzel I. Microsamal prostaglandin E2 synthase-1 as a new macromolecular drug target in the prevention of inflammation and cancer. Anti-Cancer Agents Med Chem. 2019; 19(10): 1205-1222. [CrossRef]
10. [10] Kadi AA, El-Brollosy NR, Al-Deeb OA, Habib EE, Ibrahim TM, El-Emam AA. Synthesis,antimicrobial and a antiinflammatory activities of novel 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and 2-(1-adamantylamino)-5- substitued-1,3,4-thiadiazoles. Eur J Med Chem. 2007; 42: 235-242. [CrossRef]
11. [11] Ahsan MJ, Samy JG, Khalilullah MS, Nomani MS, Saraswat P, Gaur R, Singh A. Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents. Bioorg Med Chem Lett. 2011; 21: 7246-7250. [CrossRef]
12. [12] Pinna GA, Murineddu G, Murruzzu C, Zuco V, Zunino F, Cappelletti G, Artali R, Cignarella G, Solano L, Villa S. Synthesis, modelling and antimitotic porperties of tricyclic systems characterized by a 2-(5-phenyl-1-H-pyyrol-3-yl)- 1,3,4-oxadiazole moeity. ChemMedChem. 2009; 4: 998-1009. [CrossRef]
13. [13] Zhang XM, Qui M, Sun J, Zhang YB, Yang YS, Wang XL, Zhu HL. Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan moeity as potential anticancer agents. Bioorg Med Chem. 2011; 19: 6518-6524. [CrossRef]
14. [14] Du QR, Li DD, Pi YZ, Li JR, Sun J, Fang F, Zhong WQ, Gong HB, Zhu HL. Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents. Bioorg Med Chem. 2013: 21; 2286-2297. [CrossRef]
15. [15] Bajaj S, Roy PP, Singh J. Synthesis, thmynidine phosphorylase inhibitory and computational study of novel 1,3,4- oxadizole-2-thione derivatives as a potential anticancer agents. Comput Biol Chem. 2018; 74: 151-160. [CrossRef]
16. [16] Kulabaş N, Tatar E, Özakpınar ÖB, Özsavcı D, Pannecouque C, De Clercq E, Küçükgüzel İ. Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells. Eur J Med Chem. 2016; 121: 58-70. [CrossRef]
17. [17] Gahani U, Ullah N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site. Bioorg Med Chem. 2010; 18(11): 4042-4048. [CrossRef]
18. [18] Zhang LR, Liu ZJ, Zhang H, Sun J, Luo Y, Zhao TT, Gong HB, Zhu HL. Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives. Bioorg Med Chem. 2012; 20: 3615-3621. [CrossRef]
19. [19] Zhang S, Luo Y, He LQ, Liu ZJ, Jiang AQ, Yang YH, Zhu HL. Synthesis, biological evaluation and molecular docking studies of novel 1,3,4-oxadiazole derivatives possesing benzotriazole moiety as FAK inhibitors with anticancer activity. Bioorg Med Chem. 2013; 21: 3723-3729. [CrossRef]
20. [20] Yurttaş L, Bülbül EF, Tekinkoca S, Demirayak Ş. Antimicrobial activity evaluation of new 1,3,4-oxadiazole derivatives. Acta Pharm Sci. 2017; 55(2): 45-54. [CrossRef]
21. [21] He S, Li C, Liu Y, Lai L. Discovery of highly potent microsomal prostaglandin E2 synthase-1 inhibitors using the active conformation structural model and virtual screen. J Med Chem. 2013; 56: 3296-3309. [CrossRef]
22. [22] Abd-Ellah SH, Abdel-Aziz M, Shoman ME, Beshr EAM, Kaoud TS, Ahmed ASFF. New 1,3,4-oxadiazole/oxime hybrids: Design, synthesis, anti-inflammatory, COX inhibitory and ulcerogenic liability. Bioorg Chem. 2017; 74: 15- 29. [CrossRef]
23. [23] Wu W, Chen Q, Tai A, Jiang G, Ouyang G. Synthesis and antiviral activity of 2-substitutedmethylthio-5-(4-amino-2- methylpyrimidin-5-yl)-1,3,4-oxadiazole derivatives. Bioorg Med Chem Lett. 2015; 25: 2243-2246. [CrossRef]
24. [24] Kordali S, Cakir A, Ozer H, Ckamakcı R, Kesdek M, Mete E. Antifungal, phytotoxic and insecticidal proporteis of essentiaol oil isolated Turkish Orifanum acutidens and its three components carvacrol, thymol and p-cymene. Biosource Tech. 2008; 99: 8788-8795. [CrossRef]
25. [25] Guarda A, Rubilar JF, Miltz J, Galotto MJ. The antimicrobial activity of microencapsulated thymol and carvacrol. J Food Microbiol. 2011; 146: 144-150. [CrossRef]
26. [26] Ghomi JS, Ebrahimabadi AH, Bidgoli ZD, Batooli H. GC/MS analysis and in vitro antioxidant activity of essantial oil and methanol extracts of Thymus caramicus jalas and its main constituent carvacrol. Food Chem. 2009; 115: 1524- 1528. [CrossRef]
27. [27] Yin QH, Yan FX, Zu XY, Wu YH, Wu XP, Liao MC, Deng SW, Yin LI, Zhuang YZ. Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology. 2012; 64: 43-51. [CrossRef]
28. [28] Fan K, Xiaolei L, Cao Y, Qi H, Li L, Zhang Q, Sun H. Carvacrol inhibits proliferation and induces apoptosis in human colon cancer cells. Anti-Cancer Drugs. 2015; 26(8): 813-823. [CrossRef]
29. [29] Günes-Bayır A, Kızıltan HS, Kocyigit A, Güler EM, Karatas E, Toprak A. Effects of natural phenolic compound carvacrol on the human gastric adenocarcinoma (AGS) cells in vitro. Anti-Cancer Drugs. 2017; 28: 522-530. [CrossRef]
30. [30] Wagner H, Wierer M, Bauer R. In vitro inhibition of prostaglandin biosynthesis by essential oils and phenolic compounds. Planta Med. 1986; 52: 184-187.
31. [31] Landa P, Kokoska L, Pribylova M, Vanek T, Marsik P. In vitro anti-inflammatory activity of carvacrol: Inhibitory effect on COX-2 catalyzed prostaglandin E2 biosynthesis. Arch Pharm Res 2009; 32: 75-78. [CrossRef]
32. [32] Lima MDS, Quintans-Junior L, Santana WAD, Kaneto CM, Soaers MBP, Villareal CF. Anti-inflammatory effects of carvacrol: Evidence for a key role of interleukin-10. Eur J Pharm. 2013; 699: 112-117. [CrossRef]
33. [33] Riendeau D, Aspiotis R, Ethier D, Gareau Y, Grimm EL, Guay J, Guiral S, Juteau H, Mancini JA, Methot N, Rubin J, Friesen RW. Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg Med Chem Lett. 2005; 15: 3352-3355. [CrossRef]
34. [34] Cote B, Boulet L, Brideau C, Claveau D, Ethier D, Frenette R, Gagnon M, Giroux A, Guay J, Guiral S, Mancini J, Martins E, Masse F, Methot N, Riendeau D, Rubin J, Xu D, Yu H, Ducharme Y, Friesen RW. Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors. Bioorg Med Chem Lett. 2007; 17: 6816−6820. [CrossRef]
35. [35] Wu YC, Su LJ, Wang HW, Lin CFJ, Hsu WH, Chou TY, Huang CFY, Lu CL, Hsueh CT. Co-Overexpression of Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 adversely affects the prospective survival in nonsmall cell lung cancer. J Thorac Oncol. 2010; 5(8): 1167-1174. [CrossRef]
36. [36] Chiasson JF, Boulet L, Brideau C, Chau A, Claveau D, Cote B, Ethier D, Giroux A, Guay J, Guiral S, Mancini J, Masse F, Methot N, Riendeau D, Roy P, Rubin J, Xu D, Yu H, Ducharme Y, Friesen RW. Trisubstituted ureas as potent and selective mPGES-1 inhibitors. Bioorg Med Chem Lett. 2011; 21: 1488−1492. [CrossRef]
37. [37] Shiro T, Takahashi H, Kakiguchi K, Inoue Y, Masuda K, Nagata H, Tobe M. Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg Med Chem Lett. 2012; 22: 285−288. [CrossRef]
38. [38] Shiro T, Kakiguchi K, Takahashi H, Nagata H, Tobe M. Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors. Bioorg. Med Chem. 2013; 21: 2068−2078. [CrossRef]
39. [39] Shiro T, Kakiguchi K, Takahashi H, Nagata H, Tobe M. 7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors. Bioorg Med Chem. 2013; 21: 2868−2878. [CrossRef]
40. [40] Lauro G, Tortorella P, Bertamino A, Ostacolo C, Koeerle A, Fischer K, Brun I, Terracciano S, Monterrey IMG, Tauro M, Loiodice F, Novellino E, Riccio R, Werz O, Campiglia P, Bifulco G. Structure-based design of microsomal prostaglandin E2 synthase (mPGES-1) inhibitors using a virtual fragment growing optimization scheme. ChemMedChem. 2016; 11: 612-619. [CrossRef]
41. [41] Larsson K, Jakobbson PJ. Inhibition of microsamal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostg Oth Lip M. 2015; 120: 161-165. [CrossRef]
42. [42] Koeberle A, Laufer SA, Werz O. Design and development of microsomal prostaglandin E2 synthase-1 inhibitors: challenges and future directions. J Med Chem. 2016; 59: 5970-5986. [CrossRef]
43. [43] Jin Y, Smith CL, Hu L, Campanale KM, Stoltz R Huffman Jr LG, McNearney TA, Yang XY, Ackermann BL, Dean R, Regev A, Landschulz W. Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandine synthase 1 inhibitor, with celecoxib. Clin Pharmacol Ther. 2016; 99; 274-284. [CrossRef]
44. [44] Sant S, Tandon M, Menon V, Gudi G, Kattige V, Joshi NK, Korukonda K, Dolberg OL. GRC 27864, novel, microsomal prostaglandin E synthase-1 enzyme inhibitor: phase 1 study to evaluate safety, PK and biomarkers in healthy, adult subjects. Osteoarthr Cartilage. 2018; 26(1): 351-352. [CrossRef]
45. [45] Ding K, Zhou Z, Hou S, Yuan Y, Zhou S, Zheng J, Chen C, Loftin C, Zheng F, Zhan CG. Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs. Sci Rep. 2018; 8: 5205. [CrossRef]
46. [46] Waltenberger B, Wiechmann K, Bauer J, Markt P, Noha SM, Wolber G, Rollinger JM, Werz O, Schuster D, Stuppner H. Pharmacophore modelling and virtual screening for novel acidic inhibitors of microsomal prostglandin E2 synthase-1 (mPGES-1). J Med Chem. 2011; 54: 3163–3174. [CrossRef]
47. [47] Bergqvist F, Ossiåpva E, Weway K, Idprg H, Checa A, Englund K, Englund P, Khoonsari PE, Kultima K, Wheelock CE, Larsson K, Korotkova M, Jakobsson PJ. Inhibition of mPGES-1 or COX-2 results in different proteomic and lipidomic profiles in A549 lung cancer cells. Front Pharmocol. 2019; 10: 636. [CrossRef]
48. [48] Gür ZT, Çalışkan B, Garscha U, Olgaç A, Schubert US, Gerstmeier J, Werz O, Banoğlu E. Identificationof multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning og the FLAP inhibitor BRP-7. Eur J Med Chem. 2018; 150: 876-899. [CrossRef]
49. [49] Bagul SD, Rajput JD, Tadavi SK, Bendre RS. Design, synthesis and biological activities of novel 5-isopropyl-2 methylphenolhyrazide-based sulfonamide derivatives. Res Chem Intermed. 2016; 43(4): 2241-2252. [CrossRef]
50. [50] Lacasse G, Muchowski JM. Five-Membered Heterocylic Thions. Part II. Oxadiazole-2-thione. Can J Chem. 1972; 50: 3082-3083.
51. [51] Öztürk S, Akkurt M, Cansız A, Çetin A, Şekerci M, Heinemann FW. 5-(Furan-2-yl)-1,3,4-oxadiazole-2(3H)-thione. Acta Crystallogr B. 2004; E60: o322-o323. [CrossRef]
52. [52] Horning DE, Muchowski JM. Five-membered heterocyclic thiones. Part I. 1,3,4-oxadiazole-2-thione. Canadian J Chem. 1972; 50: 3079.
53. [53] Tomi IHR, Al-Qaisi AHJ, Al-Qaisi ZHJ. Synthesis, characterization and effect of bis 1,3,4-oxadiazole containing glycine moeity on the activity of some trasnferase enzymes. J King Saud Univ Sci. 2011; 23(3): 23-33. [CrossRef]
54. [54] Gürsoy A, Demirayak Ş, Cesur Z, Reisch J, Ötük G. Synthesis of some new hyrdazide-hydrazones, thiosemicarbazides, thiadiazoles, triazoles and their derivatives as possible antimicrobials. Pharmazie. 1990; 21(42): 246-250. [CrossRef]
55. [55] Hamza A, Zhao X, Tong M, Tong M, Tai HH, Zhan CG. Novel human mPGES-1 inhibitors identifed through structure-based virtual screening. Bioorg Med Chem. 2011; 19(20); 6077-6086. [CrossRef]
56. [56] Dhanjal JK, Sreenidhi AK, Bafna K, Katiyar SP, Goyal S, Grover A, Sundar D. Computational structure-based de novo design of hypothetical inhibitors against the anti-inflammatory target COX-2. PloS ONE. 2015; 10(8), e0134691. [CrossRef]
57. [57] Morris GM, Ruth H, Lindstorm W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comp Chem. 2009; 30(16): 2785–2791. [CrossRef]
58. [58] SwissADME, http://www.swissadme.ch/ (accessed on 29 Jan 2020).
59. [59] Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherbone B, Cooper I. Rate´limited steps of human oral absorption and QSAR studies. Pharm Res. 2002; 19(10): 1446-1457. [CrossRef]
60. [60] Fromm MF. P-glycoprotein: A defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000; 38: 69–74. [CrossRef]
61. [61] Kaplan YC, Gelal A. The role of p-glycoprotein in pharmacokinetics and toxicokinetic. Turkiye Klinikleri J Surg Med Sci. 2006; 2(46): 33-38.
62. [62] Daina A, Zoete V. A BOILED-Egg to predict gastroinstestinal absorption and brain penetration of small molecules. ChemMedChem. 2016; 11(11): 1117-1121. [CrossRef]
63. [63] ACD Labs, https://www.acdlabs.com/index.php (accessed on 29 Jan 2020).
64. [64] Manjunatha K, Poojary B, Lobo PL, Fernandes J, Kumari NS. Synthesis and biological evaluation of some 1,3,4- oxadiazole derivatives. Eur J Med Chem. 2010; 45: 5225-5233. [CrossRef]
65. [65] Dassault Systèmes BIOVIA Discovery Studio 2017 R2: A comprehensive predictive science application for the Life Sciences. San Diego, CA, USA. (2017).
66. [66] Cingolani G, Panella A, Perrone MG, Vitale P, Di Mauro G, Fortuna CG, Armen RE, Ferorelli S, Smith WL, Scilimati A. Structural basis for selective inhibition of cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5- chlorofuran-2-yl)-5-methyl-4-phenylisoxazole. Eur J Med Chem. 2017; 138: 661-668. [CrossRef]
67. [67] Lucido MJ, Orlando BJ, Vecchio AJ, Malkowski MG. Crystal structure of aspirin-acetylated human Cyclooxygenase2: Insight into the formation of products with reversed stereochemistry. Biochemistry. 2016; 55(8): 1226–1238. [CrossRef]
68. [68] Kuklish SL, Antonysamy S, Bhattachar SN, Chandrasekhar S, Fisher MJ, Fretland AJ, Gooding K, Harvey A, Hugnes NE, Luz JG, Manninen PR, McGee JE, Navarro A, Norman BH, Prtridge KM, Quimby SJ, Schiffler MA, Sloan AV, Warshawsky AM, York JS, Yu XP. Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorg Med Chem Lett. 2016; 26(19): 4824–4828. [CrossRef]
69. [69] Hamza A, Tong M, Abdulhameed MDM, Liu J, Goren AC, Tai HH, Zhan CG. Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: Insights from computational alanine scanning and site-directed mutagenesis. J Phys Chem B. 2010; 114: 5605–5616. [CrossRef]
70. [70] Ding K, Zhou Z, Zhou S, Yuan X, Kim K, Zhang T, Zheng X, Zheng F, Zhan CG. Design, synthesis and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1. Bioorg Med Chem Lett. 2018; 27: 858-862. [CrossRef]
71. [71] Hamza A, Zhao X, Tong M, Tai HH, Zhan CG. Bioorg Med Chem. Novel human mPGES-1 inhibitors identified through structure-based virtual screening. Bioorg Med Chem. 2011; 19: 6077-6086. [CrossRef]
72. [72] Zhou Z, Yuan Y, Zhou S, Ding K, Zheng F, Zhan CG. Selective inhibitors of human mPGES-1 from structure-based computational screening. Bioorg Med Chem Lett. 2017; 27: 3739-3743. [CrossRef]
73. [73] Harding L, Wang Z, Tai HH. Stimulation of prostaglandin E2 synthesis by interleukin-1β is amplified by interferons but inhibited by interleukin-4 in human amnion-derived WISH cells. Biochim Biophys Acta. 1996; 1310: 48-52. [CrossRef]