Govinda Raju Vadankula, Vipul V. Nilkanth, Arshad Rizvi, Sriram Yandrapally, Anushka Agarwal, Hepshibha Chirra, Rashmita Biswas, Mohammed Arifuddin*, Vijay Nema, Alvala Mallika, Shekhar C. Mande and Sharmistha Banerjee*,
{"title":"对抗结核病:合成喹啉-异烟酸酰肼杂化物作为抗结核分枝杆菌的强效先导分子。","authors":"Govinda Raju Vadankula, Vipul V. Nilkanth, Arshad Rizvi, Sriram Yandrapally, Anushka Agarwal, Hepshibha Chirra, Rashmita Biswas, Mohammed Arifuddin*, Vijay Nema, Alvala Mallika, Shekhar C. Mande and Sharmistha Banerjee*, ","doi":"10.1021/acsinfecdis.4c00277","DOIUrl":null,"url":null,"abstract":"<p >The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>) strains were performed. It demonstrated an MIC<sub>50</sub> value of 1.86 ± 0.21 μM for laboratory pathogenic <i>M.tb</i> strain H37Rv and 3.045 ± 0.813 μM for a clinical <i>M.tb</i> strain CDC1551. UH-NIP-16 also decreased the MIC<sub>50</sub> values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR <i>M.tb</i> strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse <i>M.tb</i> proteins showed high binding affinities with multiple <i>M.tb</i> proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against <i>M.tb</i>, both alone and in combination with first-line drugs.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis\",\"authors\":\"Govinda Raju Vadankula, Vipul V. Nilkanth, Arshad Rizvi, Sriram Yandrapally, Anushka Agarwal, Hepshibha Chirra, Rashmita Biswas, Mohammed Arifuddin*, Vijay Nema, Alvala Mallika, Shekhar C. 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Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis
The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 μM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 μM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.