Tetrazolopyrimidine-tethered phenothiazine molecular hybrids: synthesis, biological and molecular docking studies†

Abstract

Molecular hybrids integrating phenothiazine and tetrazolopyrimidine structural motifs (5a–5c, 6a–6c, 7a–7b, 8a and 9a–9b) were designed and synthesized from phenothiazine by adopting a multi-step synthetic strategy involving alkylation, Vilsmeier–Haack, and a one-pot multi-component reaction. Spectroscopic and physical techniques were used to elucidate the structures of all the molecular hybrids. Appreciable radical scavenging potency was realized (up to 82%) for all the chemical entities with respect to a standard, ascorbic acid, and the one having the ethyl substituent on the N- of the phenothiazine unit 5a offered the highest potency (∼82%) among all the tested ones as evidenced from the DPPH radical scavenging evaluation. In addition, greater cytotoxic activities were realized for the molecular hybrids 5a–5c, 6a and 6c amongst the ones synthesized, and particularly, the hybrid 6a exhibited the highest potency as a result of the method of Cell-Titre Glo Luminescent cytotoxicity evaluation. Besides, an appreciable binding affinity (−8.72 kcal mol⁻¹; RMSD/ub and RMSD/lb equalled zero) resulted from the most potent cytotoxic hybrid 6a when subjected to molecular docking with B-cell lymphoma 2.