Ultrasound assisted synthesis of tetrazole based pyrazolines and isoxazolines as potent anticancer agents via inhibition of tubulin polymerization

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127592. doi: 10.1016/j.bmcl.2020.127592.

Vidya S Dofe ¹, Aniket P Sarkate ², Shailee V Tiwari ³, Deepak K Lokwani ⁴, Kshipra S Karnik ⁵, Ishwari A Kale ⁵, Suneel Dodamani ⁶, Sunil S Jalalpure ⁷, Prasad V L S Burra ⁸

Affiliations

1 Department of Chemistry, Deogiri College, Aurangabad 431 005, Maharashtra, India.
2 Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, India. Electronic address: dbsaniket09@gmail.com.
3 Department of Pharmaceutical Chemistry, Durgamata Institute of Pharmacy, Dharmapuri, Parbhani 431401, MS, India.
4 Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education & Research, Shirpur 425405, MS, India.
5 Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, India.
6 Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi 590010, Karnataka, India.
7 Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi 590010, Karnataka, India; KLE College of Pharmacy, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi 590010, Karnataka, India.
8 Department of Biotechnology, KLEF University, Vaddeswaram, AP 522502, India.

PMID: 33010448 DOI: 10.1016/j.bmcl.2020.127592

Abstract

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by ¹H NMR, ¹³C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC₅₀ values (0.78-3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents.

Keywords

Anticancer; Docking; Isoxazoline; Pyrazoline; Tetrazole; Tubulin; Ultrasound.

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