| Autor: |
Vadankula GR; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India., Nilkanth VV; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India.; Bioinformatics Centre, Savitribai Phule Pune University, Pune 411007, India., Rizvi A; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India., Yandrapally S; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India., Agarwal A; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India., Chirra H; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Biswas R; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Arifuddin M; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Nema V; Molecular Biology Division, ICMR-National Institute for Translational Virology and AIDS Research, Pune 411026, India., Mallika A; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India., Mande SC; National Centre for Cell Science, Pune 411007, India.; Bioinformatics Centre, Savitribai Phule Pune University, Pune 411007, India., Banerjee S; Laboratory of Molecular Pathogenesis, Department of Biochemistry, School of Life Sciences, University of Hyderabad (UoH), Hyderabad 500046, India. |
| Abstrakt: |
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 MIC 50 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 MIC 50 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. |
