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

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 (similar to 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. Molecular hybrids integrating phenothiazine and tetrazolopyrimidine structural motifs were designed, synthesized through a one-pot multi-component reaction and, evaluated for their radical scavenging, cytotoxicity and molecular docking studies.