article · Molecules
Two series of isatin-tethered quinoline compounds, designated Q6a to h and Q8a to h, were designed and synthesised as potential anti-tubercular agents. The molecular design used bioisosteric replacement to substitute the 3,4,5-trimethoxy-benzylidene group of an earlier quinoline lead compound with an isatin scaffold. The second series introduced either methyl or benzyl substitutions onto the isatin nitrogen. Both series of conjugates were evaluated for their biological action against drug-susceptible, multi-drug resistant, and extensively drug-resistant strains of Mycobacterium tuberculosis. Among the tested molecules, the N-benzyl-bearing analogue Q8b demonstrated the strongest activity, achieving minimum inhibitory concentrations of 0.06 micrograms per millilitre against susceptible strains, 0.24 micrograms per millilitre against multi-drug resistant strains, and 1.95 micrograms per millilitre against extensively drug-resistant strains.
Tuberculosis strains that withstand conventional antibiotics, including multi-drug resistant and extensively drug-resistant forms, pose severe threats to global public health. Identifying new molecular scaffolds capable of inhibiting these resilient bacteria is critical for future medicine. Demonstrating potent inhibitory action against both susceptible and highly resistant strains shows that isatin-quinoline hybrids hold promise for the continued search for viable therapeutic options.
This research represents early-stage laboratory drug discovery focused on synthesis and in vitro screening. The findings could serve pharmaceutical companies, academic drug discovery centres, and medicinal chemists looking for new hit-to-lead candidates targeting resistant tuberculosis. Substantial further work, including toxicity assessment, pharmacokinetic profiling, and in vivo efficacy testing, is necessary before these molecules could advance toward clinical development or commercial therapeutic pipelines.
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We describe the design and synthesis of two isatin-tethered quinolines series (Q6a–h and Q8a–h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a–h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a–h. All of the designed quinoilne-isatin conjugates Q6a–h and Q8a–h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.
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DOI: 10.3390/molecules27248807
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