Exploration of 1,3,4-Thiadiazole Bearing Quinolin-2(1H)-One Hybrids as Potent Antimycobacterial Agents: Design,...

The development of novel quinolin-2(1H)-one-fused 1,3,4-thiadiazole heterocyclic hybrids was achieved through structural optimization as potential antimicrobial/anti- TB agents.

A condensation reaction of 5-amino-1,3,4-thiadiazole and various aldehydes in glacial acetic acid was carried out to synthesize substituted quinolinone derivatives containing a thioethoxy linker. In this study, new quinolinones containing thiadiazole skeletons were synthesized with potential for further biological evaluation. Subsequently, molecular docking and ADME-Tox analyses were performed to predict the pharmacological and pharmacokinetic properties of the synthesized molecules.

According to the activity results obtained, the tested compounds 6e and 6k showed significant antibacterial activity versus B. subtilis with MIC values of 3.55 ± 1.20 and 3.98 ± 1.20 μg mL-¹ and P. aeruginosa strain MIC values ranging from 2.90 ± 0.93 to 4.28 ± 0.47 μg mL-¹ in comparison to gatifloxacin (MIC = 4.03 ± 0.56 and 3.10 ± 0.99 μg mL-¹, respectively). These hybrids represent a promising new class of anti-tubercular agents, as demonstrated by the exceptional in vitro activity of compounds 6e and 6i (MIC = 1.69 ± 1.10 and 1.57 ± 0.34 μg mL-¹), which show potency equivalent to the standard drug streptomycin (MIC = 1.56 μg mL-¹). Furthermore, the physicochemical and ADME filtration molecular properties, estimation of bioactivity, and toxicity scores of these scaffolds were evaluated. The amalgamation of molecular docking of ligands 6b, 6e, 6i, and 6k is attributable to their robust and efficacious interactions at the active sites of the potent enzymes for antibacterial (1U1Z) and anti-TB (4FDO) actions, respectively.

Three-pot condensation processes were used to create the target compounds, which were then analyzed using HRMS, ¹H-NMR, and ¹³C-NMR methods. The strong binding interactions observed for selected derivatives suggest promising antibacterial and antitubercular activity, consistent with the known bioactivity of quinolinone and thiadiazole-based systems.

This study led to the successful synthesis of novel quinolin-2(1H)-one-fused 1,3,4- thiadiazoles.