Design and Discovery of Substituted 1,3,4-Thiadiazole-1,3,5-Triazine Hybrids as Human Immunodeficiency Virus-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Anti-SARS-CoV-2 and Antibacterial Activities.

A new series of substituted 1,3,4-thiadiazole-1,3,5-triazine hybrids was rationally designed, synthesized, and evaluated for their antiviral and antibacterial potential. The target di-substituted (9a-e) and tri-substituted (11a-e) derivatives were obtained via a stepwise nucleophilic substitution strategy from cyanuric chloride and characterized by spectroscopic techniques. Molecular docking studies against human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) revealed that para-substituted analogs displayed superior binding within the non-nucleoside reverse transcriptase inhibitor pocket through key hydrogen bonding, π-π stacking, and electrostatic interactions. In vitro evaluation identified compounds 11a as the most active candidate. Compound 11a exhibited 83.93% inhibition of RT activity at 1 μM, an EC50 of 72.7 nM, and effective suppression of HIV-1 replication in CEM-GFP T cells (85.19% p24 inhibition) with a favorable therapeutic index (TI = 471). Both compounds also demonstrated inhibition of SARS-CoV-2-induced cytopathic effects in Vero E6 cells at noncytotoxic concentrations. In addition, several derivatives showed moderate to good antibacterial activity against tested bacterial strains, with SAR analysis highlighting the importance of substituent electronics and positional effects on bioactivity. Overall, this study establishes substituted 1,3,4-thiadiazole-1,3,5-triazine hybrids as promising multifunctional scaffolds for antiviral and antibacterial drug development.