Design, synthesis, docking studies and biological screening of 2-pyrimidinyl-2, 3-dihydro-1 H-naphtho [1, 2- e][1, 3] oxazines as potent tubulin polymerization inhibitors

Rakhi Gawali; Raghunath Bhosale; Narayana Nagesh; Vijay H Masand; Shravan Jadhav; Magdi E A Zaki; Sami A Al-Hussain

doi:10.1080/07391102.2023.2266766

Design, synthesis, docking studies and biological screening of 2-pyrimidinyl-2, 3-dihydro-1 H-naphtho [1, 2- e][1, 3] oxazines as potent tubulin polymerization inhibitors

J Biomol Struct Dyn. 2023 Oct 9:1-18. doi: 10.1080/07391102.2023.2266766. Online ahead of print.

Authors

Rakhi Gawali¹, Raghunath Bhosale², Narayana Nagesh³, Vijay H Masand⁴, Shravan Jadhav¹, Magdi E A Zaki⁵, Sami A Al-Hussain⁵

Affiliations

¹ Department of Chemistry, D.B.F. Dayanand College of Arts & Science, Solapur, India.
² Organic Chemistry Research Laboratory, School of Chemical Sciences, P. A. H. Solapur University, Solapur, India.
³ CSIR-Centre for Cellular and Molecular Biology, Medical Biotechnology Complex, ANNEX II, Hyderabad, India.
⁴ Department of Chemistry, Vidya Bharati Mahavidyalaya, Amravati, India.
⁵ Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.

PMID: 37811783
DOI: 10.1080/07391102.2023.2266766

Abstract

A series of novel substituted 2-pyrimidinyl-2,3-dihydro-1H-naphtho[1,2-e][1, 3]oxazine analogs have been designed and synthesized based on structure-activity relationships from 2-naphthol, substituted pyrimidinyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were evaluated for their in vitro cytotoxicity, cell cycle assay and their inhibitory effect on tubulin polymerization. From the MTT assay, it is clear that most of the synthesized compounds displayed potent cytotoxic activities on HeLa (cervical cancer) and B16F10 (melanoma) cancerous cell lines. The compounds 6b and 6k were found to be more effective against HeLa cell lines and exhibited significant cytotoxicity (with IC₅₀ values 1.26 ± 0.12 µM and 1.16 ± 0.27 µM respectively), accumulation of HeLa cells in G2/M phase and exhibiting induced apoptosis. The immunohistochemistry and fluorescence assays showed that these compounds 6b and 6k inhibited the microtubule assembly in human cervical cancer cells (HeLa) at 2 µM concentration. Furthermore, molecular docking studies of these molecules revealed their better-fit potential as anticancer molecules and have a high affinity for colchicine binding site, indicating more inhibitory potential at the cellular level. Our studies suggest that the newly synthesized compounds may become promising leads for the development of new anti-cancer agents.Communicated by Ramaswamy H. Sarma.

Keywords: 2-Pyrimidinyl naphthoxazine derivative; anti-cancer; cell cycle assay; cell viability; cytotoxicity; molecular docking; tubulin polymerization inhibition assay.