Thiourea-Based Compounds Effectiveness Against the Growth of Mycobacterium kansasii: Synthesis, Biological Activity, and Computational Analysis

Mycobacterium kansasii (Mkan) is a nontuberculous mycobacterium (NTM) commonly found in aquatic environments and is responsible for chronic pulmonary infections resembling tuberculosis. Treatment requires multiple antibiotics for at least 12 months, highlighting the challenge in managing Mkan infections. In this study, 50 thiourea derivatives were synthesized and evaluated for their cytotoxic and inhibitory effects on bacterial growth in culture and in infected macrophages using Mkan strains with varying virulence levels. In silico studies explored the structure–activity relationship (SAR) and the pharmacokinetic and toxicological profiles of the most active thiourea derivatives. As a result, 15 derivatives showed promising inhibitory activity against the reference strain, Mkan 12478. Of these, derivatives 2, 47, and 49 also significantly inhibited clinical isolates 10953 and 8835 without displaying cytotoxic effects. Furthermore, these three derivatives could inhibit intracellular mycobacterial growth in RAW 264.7 macrophages infected with strains 12478 or 8835. SAR studies revealed molecular volume and polar surface (PSA) area as important features for these thiourea derivatives, directly correlating with their antimycobacterial profile. In silico studies indicated that these compounds are potentially suitable for oral administration and have less toxicological effects than rifampicin, providing a safer alternative for antimycobacterial treatment. In conclusion, our findings suggest that thiourea derivatives 2, 47, and 49 are promising antimycobacterial agents for treating infections caused by Mkan.