Synthesis, Cytotoxic Evaluation, and Molecular Docking Studies of New Oxadiazole Analogues

Title:Synthesis, Cytotoxic Evaluation, and Molecular Docking Studies of New Oxadiazole Analogues

Volume: 15 Issue: 1

Author(s): Mohamed Jawed Ahsan*, Raghunath Prasad Yadav, Saroj Saini, Mohd. Zaheen Hassan, Mohammed Afroz Bakht, Surender Singh Jadav, Abdulmalik Bin Saleh Al-Tamimi, Mohammed H. Geesi, Md Yousuf Ansari, Habibullah Khalilullah and Yassine Riadi

Affiliation:

• Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari Circle, Jaipur, Rajasthan 302 039,India

Keywords: Anticancer agent, cytotoxic agents, oxadiazoles, one dose assay, molecular docking, sulforhodamine B assay.

Abstract: Background: Cancer is one of the major health diseases worldwide with an approximately 14 million new cases of cancer and 8.2 million cancer related death tolls were reported in 2012. The major complications associated with chemotherapy are limited efficacy, selectivity, safety as well as higher cost, emergence of drug resistant cancer, and genotoxicity. Today we need more effective and safer cytotoxic agents to combat cancer.

Method: Two new series of N-(2,6-dimethylphenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–g) and N-{[5- aryl-1,3,4-oxadiazol-2-yl]methyl}-2,6-dimethylaniline (4h-n) were designed and synthesized based on the structure of IMC-038525 (tubulin polymerization inhibitor) and NSC 777948 as cytotoxic agents. The cytotoxicity of eight compounds was carried out as per National Cancer Institute (NCI US) protocol on nearly 60 cancer cell lines, while the cytotoxicity of five compounds was carried out as per Sulforhodamine B assay on two breast cancer cell lines. The molecular docking studies implying tubulin inhibition were also carried out to observe the binding mode of new oxadiazoles.

Results: N-(2,6-Dimethylphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (4b) showed significant cytotoxicity with comparatively higher sensitivity towards colon cancer (HT29), melanoma (LOX IMVI), leukemia (RPMI-8226), and melanoma (M14), with percent growth inhibitions (% GIs) of 80.99, 75.05, 63.25, and 62.19 respectively. Compound 4b showed better cytotoxicity than the standard drug imatinib. Further compound 4b showed maximum docking score and was found to have different binding mode than the rest of the compounds at the colchicine binding site of tubulin enzyme with a hydrogen bonding between NH with carbonyl oxygen of Thr353 (bond length = 3.05A). The hydrophilicity of compound 4b was another parameter that might play a major role and made it most effective when compared to the rest of the compounds.

Conclusion: The oxadiazoles reported herein are cytotoxic agents. These findings may be helpful in future drug design of more potent cytotoxic agents.

Cite this article as:

Ahsan Jawed Mohamed *, Yadav Prasad Raghunath , Saini Saroj , Hassan Zaheen Mohd. , Bakht Afroz Mohammed , Jadav Singh Surender , Saleh Al-Tamimi Bin Abdulmalik , Geesi H. Mohammed , Ansari Yousuf Md , Khalilullah Habibullah and Riadi Yassine , Synthesis, Cytotoxic Evaluation, and Molecular Docking Studies of New Oxadiazole Analogues, Letters in Organic Chemistry 2018; 15 (1) . https://dx.doi.org/10.2174/1570178614666170704103315