SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development

Poce, Giovanna; Cocozza, Martina; Consalvi, Sara; Biava, Mariangela

doi:10.1016/j.ejmech.2014.08.066

Cited by 48 publications

(25 citation statements)

References 136 publications

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“…And finally, we zeroed upon the piperidine moiety. Isoniazid (INH) ( 1.1 ) is a well‐known antitubercular drug with pyridine scaffold and besides this, many six‐membered nitrogen heterocycles have been reported as a promising lead against Mycobacterium tuberculosis , especially as EACP reductase inhibitor . It has been found that 1,4‐di‐substituted piperidine derivative compound 1.2 (Figure ) has more potent antitubercular activity than the 1‐substituted piperidine derivative compound 1.3 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Kumar¹,

Rajappan²,

Sriram

et al. 2019

Archiv der Pharmazie

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Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration.HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 μg/ml). Compound R7 was found to be moderately active with an IC 50 of 2.1 ± 0.04 μM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC 50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.

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Section: Introductionmentioning

confidence: 99%

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Kumar¹,

Rajappan²,

Sriram

et al. 2019

Archiv der Pharmazie

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“…The current first‐line treatment regimen comprises isoniazid (INH), ethambutol (EMB), pyrazinamide and rifampicin (RIF) administered for 2 months followed by INH and RIF daily for another 4 months . However, poor patient adherence has led to the emergence of resistant strains of Mtb that has grossly aggravated management of TB . Overall, the intensive and protracted chemotherapy and the growing resistance to current TB drugs underscore the urgent need for more efficient drugs coupled with improvement of treatment regimens .…”

Section: Introductionmentioning

confidence: 99%

The evaluation of the anti‐cancer drug elesclomol that forms a redox‐active copper chelate as a potential anti‐tubercular drug

et al. 2019

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The observations that the innate immune system employs copper to eliminate bacterial infection and that resistance to copper enhances virulence of Mycobacterium tuberculosis (Mtb) prompted us to examine the effects the anti‐cancer agent elesclomol on Mtb. As a bis‐thionohydrazide, elesclomol chelates with copper to form a copper complex in situ that via redox cycling of the metal ion greatly enhances oxidative stress in tumour cells. Here, we demonstrate that elesclomol is relatively potent against Mtb H37Rv with minimum inhibitory concentration of 10 μM (4 mg/L) and against multidrug resistant clinical isolates of Mtb, displays additive interactions with known tuberculosis drugs such as isoniazid and ethambutol, and a synergistic interaction with rifampicin. Controlled supplementation of elesclomol with copper in culture medium increased Mtb sensitivity by >65 fold. Overall, the activities of elesclomol in principle indicate the possibility of repurposing elesclomol or designing new thionohydrazides as potential drugs for use against Mtb. © 2019 IUBMB Life, 71(5):532–538, 2019

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“…The designed compounds consist of a two main pharmocophore units viz., quinoline and 1,2,4‐triazole. As shown in the Figure , pharmacophore I, quinoline consists of two substituents at C 2 and C 6 which enhance the pharmocological properties . In regard to pharmocophore II, it was demonstrated that different types of chemical bridges at C 4 of the triazole core eliminate the planarity, thereby improving the drug's ability and facilitate the binding to their receptor through induced fit.…”

Section: Introductionmentioning

confidence: 99%

Design, Docking, and Synthesis of Quinoline‐2H‐1,2,4‐triazol‐3(4H)‐ones as Potent Anticancer and Antitubercular Agents

et al. 2018

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A new series quinoline‐2H‐1,2,4‐triazol‐3(4H)‐ones 7 g‐n and 11 g‐n were designed and synthesized. Docking studies of title compounds with DNA (PDB: 1AU5) and with long‐chain enoyl‐acyl carrier protein reductase (InhA) enzyme (PDB ID: 4TZK) as anticancer and antitubercular targets showed good insights on the possible interactions. Further, the compounds were tested for in vitro anticancer activity against HeLa human cervix tumor cell line and also in vitro antitubercular activity against M. tuberculosis H37Rv [MTB] (ATCC‐27294). Some of the compounds exhibited promising activities in both the protocols. Hence, these compounds may be considered as pharmacological lead molecules of interest.

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SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development

Cited by 48 publications

References 136 publications

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

The evaluation of the anti‐cancer drug elesclomol that forms a redox‐active copper chelate as a potential anti‐tubercular drug

Design, Docking, and Synthesis of Quinoline‐2H‐1,2,4‐triazol‐3(4H)‐ones as Potent Anticancer and Antitubercular Agents

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