Title:Rationale Design, Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies of 1,3,4-oxadiazole Analogues
VOLUME: 18 ISSUE: 1
Author(s):Mohamed Jawed Ahsan*, Arun Choupra, Rakesh Kumar Sharma, Surender Singh Jadav, Pannala Padmaja, Mohd. Zaheen Hassan, Abdulmalik Bin Saleh Al-Tamimi, Mohammed H. Geesi and Mohammed Afroz Bakht
Affiliation:Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 039, Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 039, Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 039, Department of Pharmaceutical Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835 215, Department of Chemistry, JNTUH College of Engineering, Kukatpally, Hyderabad (T.S), 500 085, Department of Pharmaceutical Chemistry, Alwar Pharnacy College, Alwar, Rajasthan 301 030, Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box- 173, Al-Kharj 11942, Department of Chemistry, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, P.O. Box 83, Al-Kharj 11942, Department of Chemistry, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, P.O. Box 83, Al-Kharj 11942
Keywords:Anticancer agents, cancer cell lines, cytotoxicity, one-dose assay, oxadiazole analogues, 5-dose assay, imatinib, gefitinib, IMC-
038525.
Abstract:Background: 1,3,4-Oxadiazole heterocycles possess a broad spectrum of biological activities. They
were reported as potent cytotoxic agents and tubulin inhibitors; hence it is of great interest to explore new
oxadiazoles as cytotoxic agents targeting tubulin polymerization.
Objective: Two new series of oxadiazoles (5a-h and 12a-h) were synthesized, structurally related to the heterocyclic
linked aryl core of IMC-038525, NSC 776715, and NSC 776716, with further modification by incorporating
methylene linker.
Method: The 2,5-disubstituted-1,3,4-oxadiazoles (5a-h and 12a-h) were synthesized by refluxing an equimolar
mixture of the intermediates [(4) and (8a-d)] and aromatic aldehydes in water-ethanol system using sodium
bisulphite catalyst. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI
US) Protocol, while the tubulin polymerization assay kits from Cytoskeleton ™(bk011p) was used to perform an
in vitro tubulin polymerization assay.
Results: 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)phenol (5f) and 2-[(2,4-dichlorophenoxy)
methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity with the mean percent
growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 µM drug concentrations. Both the compounds (5f
and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one
dose assay. The compound 12c showed promising results in five dose assay, with GI50 values varies between
1.61 and >100 µM. Furthermore, the compounds, 5f and 12c also inhibited the polymerization of tubulin with,
an IC50 of 2.8 and 2.2 µM, respectively.
Conclusion: The oxadiazoles reported herein are tubulin inhibitors and cytotoxic agents. These findings will be
helpful in future drug design of more potent tubulin inhibitor cytotoxic agents.
