Design, synthesis, and antimicrobial evaluation of heteroaromatic or acyl-substituted benzenesulfonamide-linked aminoquinolinequinones

A series of aminated quinolonequinones (AQQ1-13) was synthesized from quinolinequinone and substituted aromatic amines containing a sulfonamide group with conformationally restricted heterocyclic structures or an acyl group. The obtained AQQs were characterized by various spectroscopic techniques including FTIR, NMR, and MS analyses. Structural modifications of the sulfonamide group in these compounds were selected by introducing various heterocyclic substituents, such as isoxazole, thiadiazole, pyridine, pyrimidine, pyrazine, and pyridazine, or by attaching acyl groups (acetyl or benzamide) with different substituents. Some of the synthesized AQQs exhibited antifungal activity against the tested strains, with potencies comparable to the reference drugs under the tested conditions. Noticeably, AQQ5 with thiadiazole moiety attached to the sulfonamide group showed inhibitory activity against C. albicans (MIC: 19.53 µg/mL). The most active compound AQQ5 also showed the best antifungal potency towards to other two fungi (C. parapsilosis and C. tropicalis). However, it should be noted that antifungal activity was evaluated only against ATCC strains. Considering the increasing prevalence of antifungal resistance, these results may not fully reflect the efficacy against clinical isolates. Antifungal resistance may render the antifungal activity already seen against ATCC strains ineffective in clinical isolates. Yet the putative target, farnesyl pyrophosphate synthase identified through in silico protocols suggests that farnesyl pyrophosphate synthase may be a potential target, warranting further experimental validation.