2. Academic Validation
  3. Synthesis and screening of novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines as antiproliferative and tubulin polymerization inhibitors

Synthesis and screening of novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines as antiproliferative and tubulin polymerization inhibitors

  • Bioorg Med Chem. 2022 Oct 15:72:116976. doi: 10.1016/j.bmc.2022.116976.
Ashish Ranjan Dwivedi 1,  Suraj Singh Rawat 2,  Vijay Kumar 3,  Naveen Kumar 3,  Piyush Anand 1,  Ravi Prakash Yadav 4,  Somesh Baranwal 4,  Amit Prasad 5,  Vinod Kumar 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151401, India; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India.
  • 2 School of Basic Sciences, Indian Institute of Technology, Mandi, HP 175005, India.
  • 3 Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India.
  • 4 Department of Microbiology, School of Biological Sciences, Central University of Punjab, Bathinda, Punjab 151401, India.
  • 5 School of Basic Sciences, Indian Institute of Technology, Mandi, HP 175005, India. Electronic address: [email protected].
  • 6 Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151401, India; Laboratory of Organic and Medicinal Chemistry, Department of Chemistry, Central University of Punjab, Bathinda, Punjab 151401, India. Electronic address: [email protected].
PMID: 36067627 DOI: 10.1016/j.bmc.2022.116976
Abstract

Colchicine binding site represent a crucial target for the Anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 Cancer cell lines and normal cell line HEK-293 T. In the series, 2‑aryl group with 4‑bromophenyl substitution displayed IC50 values of 6.37 µM, 17.43 µM, 6.76 µM and 4‑chlorophenyl substitution displayed IC50 values of 2.16 µM, 8.53 µM, 10.42 µM against MCF-7, HELA and HT29 Cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, Apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated Apoptosis and lead molecule with 4‑chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent Anticancer agents.

Keywords

6,7,8-Trimethoxyquinazolines; Anticancer; Antiproliferative; Cell cycle; Tubulin polymerization inhibitors.

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