Synthesis of Novel Oxadiazole Derivatives, Molecular Properties Prediction and Molecular Docking Studies

Abstract

In this work, synthesis of novel 1,3,4-oxadiazole derivatives were reported. Good molecular properties profile was predicted for the target compounds. In drug likeness prediction, compound 4b and 8b possess the highest score of 0.31 and 0.33, respectively. Since the compounds have good bioactivity scores as kinase inhibitor, possible interactions of compounds with VEGFR-2 kinase and probable binding conformations were evaluated by molecular docking. All compounds formed hydrogen bonding interactions with Asp1046 amino acid of key residues.

Keywords

• Oxadiazole
• VEGFR-2
• docking

References

1. 1. Glomb T, Szymankiewicz K, S´wiatek P. Anti-cancer activity of derivatives of 1,3,4-oxadiazole. Molecules. 2018;23,33-61. Doi:10.3390/molecules23123361.
2. 2. Boström J, Hogner A, Llinàs A, Wellner E, Plowright AT. Oxadiazoles in Medicinal Chemistry. Journal of Medicinal Chemistry. 2012;55:1817−1830. Doi:10.1021/jm2013248.
3. 3. Zhang HZ, Zhao ZL, Zhou CH. Recent advance in oxazole-based medicinal chemistry. European Journal of Medicinal Chemistry. 2018;144:444-492. Doi: 10.1016/j.ejmech.2017.12.044.
4. 4. Akhtar J, Khan AA, Ali Z, Haider R, Shahar Yar M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. 2017;125:143-189. Doi: 10.1016/j.ejmech.2016.09.023.
5. 5. Temesgen Z, Siraj DS. Raltegravir: first in class HIV integrase inhibitor. Therapeutics and Clinical Risk Management. 2008;4:493–500. Doi: 10.2147/tcrm.s2268.
6. 6. James ND, Growcott JW. Zibotentan. Drugs of the Future. 2009;34(8):624-633. Doi: 10.1358/dof.2009.34.8.1400202.
7. 7. Jones AM, Helm JM. Emerging treatments in cystic fibrosis. Drugs. 2009;69:1903−1910. Doi: 10.2165/11318500-000000000-00000.
8. 8. Ouyang X, Piatnitski EL, Pattaropong V, Chen X, Hai-Ying H, et al. Synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines. Bioorganic and Medicinal Chemistry Letters. 2006;16:1191-1196.

9. 9. Abou-Seri SM. Synthesis and biological evaluation of novel 2,4’-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitors. European Journal of Medicinal Chemistry. 2010;45:4113–4121. Doi: 10.1016/j.ejmech.2010.05.072.
10. 10. Zhang K, Wang P, Xuan LN, Fu XY, Jing F, Li S, Liu YM, Chen BQ, Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety. Bioorganic and Medicinal Chemistry Letters. 2014;24:5154-5156. Doi: 10.1016/j.bmcl.2014.09.086.
11. 11. Pidugu VR, Yarla NS, Pedada SR, Kalle AM, Satya AK. Design and synthesis of novel hdac8 ınhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity. Bioorganic Medicinal Chemistry. 2016;24:5611–5617. Doi: 10.1016/j.bmc.2016.09.022.
12. 12. Sun J, Ren SZ, Lu XY, Li JJ, Shen FQ, Xu C, Zhu HL. Discovery of a series of 1,3,4-oxadiazole-2(3h)-thione derivatives containing piperazine skeleton as potential Fak inhibitors. Bioorganic Medicinal Chemistry. 2017;25:2593–2600. Doi: 10.1016/j.bmc.2017.03.038.
13. 13. Mohan CD, Anilkumar NC, Rangappa S, Shanmugam MK, Mishra S, Chinnathambi A, Alharbi SA, Bhattacharjee A, Sethi G, Kumar AP, Rangappa KS. Novel 1,3,4-oxadiazole induces anticancer activity by targeting nf-κb in hepatocellular carcinoma cells. Front. Oncol. 2018;8:42. Doi: 10.3389/fonc.2018.00042.
14. 14. Feinstein A, Gore PH, Reed, GL. Alkaline hydrolysis of the methyl esters of benzo[b]furan-2- and 3-carboxylic acid, benzo[b]thiophene-2- and 3-carboxylic acid, and indole-2- and 3-carboxylic acid. Journal of the Chemical Society [Section] B: Physical Organic. 1969;3:205-207.
15. 15. Kovalenko SI, Antypenko LM, Bilyi AK, Kholodnyak SV, Karpenko OV, Antypenko OM, Mykhaylova NS, Los TI, Kolomoets OS. Synthesis and anticancer activity of 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines. Scientia Pharmaceutica. 2013;81(2):359-391. Doi:10.3797/scipharm.1211-08.
16. 16. Guo Y, Xu T, Bao C, Liu Z, Fan J, Yang R, Qin S. Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA). European Journal of Pharmaceutical Sciences 2019;136:104966. Doi:10.1016/j.ejps.2019.104966.
17. 17. Molinspiration Cheminformatics, Bratislava, Slovak Republic, Available from: http://www.molinspiration.com/services/properties.html
18. 18. Drug-likeness and molecular property prediction, available from: http:// www.molsoft.com/mprop/
19. 19. Mistry SN, Shonberg J, Draper-Joyce CJ, Herenbrink CK, Michino M, Shi L, Christopoulos A, Capuano B, Scammells PJ, Lane JR. Discovery of a novel class of negative allosteric modulator of the dopamine d2 receptor through fragmentation of a bitopic ligand. Journal of Medicinal Chemistry. 2015;58:6819-6843. Doi:10.1021/acs.jmedchem.5b00585.
20. 20. Almutairi MS, Zakaria AS, Ignasius PP, Al-Wabli RI, Joe IH, Attia MI. Synthesis, spectroscopic investigations, DFT studies, molecular docking and antimicrobial potential of certain new indole-isatin molecular hybrids: Experimental and theoretical approaches. Journal of Molecular Structure. 2018;1153:333-345. Doi:10.1016/j.molstruc.2017.10.025.
21. 21. Wei Z-Y, Chi K-Q, Wanga K-S, Wub J, Liu L-P, Piao H-R. Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents. Bioorganic and Medicinal Chemistry Letters. 2018;28:1797-1803. Doi: 10.1016/j.bmcl.2018.04.021.
22. 22. Lipinski CA, Lombardo L, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 2001;46:3-26. Doi: 10.1016/s0169-409x(00)00129-0
23. 23. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper Rate-limited steps of human oral absorption and QSAR studies. I. Pharmaceutical Research. 2002;19:1446-1457. Doi:10.1023/A:1020444330011
24. 24. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. Journal of Medicinal Chemitry. 2002;45:2615-2623. Doi:10.1021/jm020017n
25. 25. Jain NK, Chourasia MK, Jain S, Jain SK. Development and characterization of engineered commensal bacteria for the delivery of enzymes. Indian Journal of Pharmaceutical Sciences. 2003;65:113-1