Synthesis, characterization, X-ray diffraction, in silico studies and in vitro biological evaluation of...

A series of thiazole-2-imines (1a-1f) with unsubstituted aryl groups or aryl groups bearing methyl, methoxy, fluoro, or nitro substituents was designed using selected structural features of thiamine as inspiration. The compounds were synthesized from monosubstituted acylthioureas and para-substituted phenacyl bromides in 82-95% yields. Various spectroscopic techniques and high-resolution mass spectrometric analysis confirmed product formation. Single-crystal X-ray diffraction of the methyl/methyl, fluoro/fluoro, and nitro/fluoro-substituted derivatives established the Z-configured scaffold. Density functional theory (DFT) calculations supported the observed experimental geometries. Flexophore analysis indicated low-to-moderate similarity to thiamine, with the nitro/fluoro-substituted derivative yielding the highest score (41%). Docking of hypothetical pyrophosphorylated derivatives and the parent thiazole-2-imines suggested that these compounds could be accommodated within selected binding pockets of thiamine-dependent enzymes and TB- or HIV-related proteins. However, these predictions do not establish antimetabolite activity or specific molecular targets. In silico absorption, distribution, metabolism, excretion, and toxicity profiling predicted no Lipinski violations, low metabolic liability, and at least 74% oral absorption. In vitro evaluation against Mycobacterium tuberculosis H37Rv showed modest antimycobacterial activity, with MIC₉₀ values ranging from 125 to 250 µM. The nitro/fluoro substituted derivative (1f) showed the strongest anti-HIV activity (IC₅₀ = 75.86 µM) and the most favourable HIV-specific selectivity index, followed by the methyl/methyl-substituted derivative (1b).