Exploring the antimicrobial properties of synthetic tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTTs) through in vitro and in silico antileishmanial and antibacterial studies

Abstract

Infectious diseases represent a significant health concern due to their high rates of morbidity and mortality. Despite significant advances in the understanding of the pathogenic infection, existing therapies to control those infections are still unsatisfactory. Herein, a total of 18 alkyl/aryl/aralkylamines or amino acids attached 1,3,5-thiadiazine-2-thiones (4a–i, 5a–g, 6 and 7) were synthesized via one pot domino synthesis and assessed their in vitro leishmanicidal and bactericidal potential. Their structures were confirmed through advanced spectroscopic techniques (¹H-NMR, ¹³C-NMR, and HRMS analysis). The compounds inhibited promastigotes of Leishmania tropica with IC₅₀ values ranging from 1.50 µg mL⁻¹ to 72.04 µg mL⁻¹, where compounds 4d (IC₅₀ = 1.50 µg mL⁻¹) and 4f (IC₅₀ = 4.61 µg mL⁻¹) exhibited the most potent inhibition. The in silico analysis showed good binding potential of both the compounds for Pteridine reductase 1 (PTR1; a crucial enzyme in the life cycle of leishmania) and acceptable physicochemical and drug-like profile. In molecular dynamics simulations, 4d showed greater potency for PTR1 with MM-PBSA estimated binding free energy of −18.72 ± 3.21 kcal mol⁻¹. Additionally, compound 7 demonstrates potent antibacterial activity against Staphylococcus aureus as compared to amoxicillin, while compounds 5g, 4c, 4d, 4e, 4f, and 5b showed significant inhibition of Klebsiella pneumoniae. These findings suggest that compound 7 exhibits selective antibacterial activity against S. aureus, whereas compound 4e demonstrates broad-spectrum potential by targeting both Gram-negative and Gram-positive bacteria. The dose-dependent inhibition observed indicates the need for further structural optimization to enhance antibacterial potency. Additionally, compounds 4d and 4f displayed dual antileishmanial and antibacterial activities, making them promising candidates for further investigation and optimization to achieve clinically relevant efficacy.