article · Journal of Enzyme Inhibition and Medicinal Chemistry
Novel hybrid chemical compounds combining isatin and nicotinohydrazide scaffolds have been synthesised and evaluated for their effectiveness against tuberculosis and respiratory bacterial pathogens. Testing against drug-susceptible Mycobacterium tuberculosis revealed that specific hybrid molecules matched the potency of the standard treatment isoniazid, achieving a minimum inhibitory concentration of 0.24 micrograms per millilitre. Two of these compounds also retained notable activity against a strain resistant to both isoniazid and streptomycin, recording a minimum inhibitory concentration of 3.9 micrograms per millilitre. In broader antibacterial screening across six strains associated with bronchitis, most of the synthesised hybrids showed strong inhibition, with Klebsiella pneumoniae proving to be the most sensitive organism. In addition, computational molecular docking indicated that the enzyme DprE1 serves as a probable biological target, illustrating how these hybrid molecules bind within the active site.
Tuberculosis remains a critical global health threat, and the rise of strains resistant to front-line antibiotics complicates clinical treatment. Discovering new compounds that can overcome resistance while inhibiting other respiratory bacterial pathogens offers potential chemical starting points for developing therapies against difficult-to-treat lung infections.
This work is at an early discovery stage, presenting novel lead compounds that could interest pharmaceutical companies and medicinal chemistry programmes developing antimicrobial therapeutics. Substantial laboratory work remains necessary before any commercial application, including safety profiling, pharmacokinetics, and in vivo efficacy validation against resistant respiratory pathogens.
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Joining the global fight against Tuberculosis, the world's most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hybrids (<b>5a-m</b> and <b>9a-c</b>) as promising anti-tubercular and antibacterial agents. The anti-tubercular activity of the target hybrids was evaluated against drug-susceptible M. tuberculosis strain (ATCC 27294) where hybrids <b>5d</b>, <b>5g</b> and <b>5h</b> were found to be as potent as INH with MIC = 0.24 µg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823) where compounds <b>5g</b> and <b>5h</b> showed excellent activity (MIC = 3.9 µg/mL). Moreover, the target hybrids were examined against six bronchitis causing-bacteria. Most derivatives exhibited excellent antibacterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49-7.81 µg/mL. Furthermore, a molecular docking study has proposed DprE1 as a probable enzymatic target for herein reported isatin-nicotinohydrazide hybrids, and explored the binding interactions within the vicinity of DprE1 active site.
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DOI: 10.1080/14756366.2020.1868450
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