Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity

Pflégr, Václav; Horváth, Lilla; Stolaříková, Jiřina; Pál, Adrian; Korduláková, Jana; Bősze, Szilvia; Vinšová, Jarmila

doi:10.1016/j.ejmech.2021.113668

Cited by 15 publications

(19 citation statements)

References 24 publications

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“…Procedure for synthesis of (E)-2-(2-isonicotinoylhydrazineylidene)propanoicacid [14,19] (2) Isoniazid (274.3 mg, 2.0 mmol) was dissolved in hot methanol (15 mL) with stirring; pyruvic acid (193.7 mg, 155 µL, 2.2 mmol) was then added dropwise. The reaction mixture was refluxed for 2 h, then let to cool at room temperature and stored for 1 h at 8 • C. Precipitate was filtered off and washed with methanol (2 × 3 mL).…”

Section: Synthesismentioning

confidence: 99%

“…13 , d, J = 4.9 Hz, H2, H6), 7.76 (2H, d, J = 4.9 Hz, H3, H5), 7.49-7.36 (5H, m, H2', H3', H4', H5', H6'), 2.14 (3H, s, CH 3 ). 13 The in vitro antimycobacterial activity of the INH derivatives 3a-3s was evaluated using a previously published method [14]. The panel of mycobacteria comprised one drug-susceptible Mycobacterium tuberculosis strain 331/88 (i.e., H 37 Rv; dilution of this strain was 10 −3 ) and two strains of nontuberculous mycobacteria: Mycobacterium avium 330/88 (resistant to INH, rifamycines, ofloxacin and ethambutol; dilution of the strain was 10 −5 ) and a clinical isolate of Mycobacterium kansasii (6509/96; dilution of the strain was 10 −4 ).…”

Section: Synthesismentioning

confidence: 99%

“…KatG protein encoded by the gene MSMEG_6384 from Mycobacterium smegmatis was overproduced in Mtb. H 37 Ra using pVV16-katG smeg construct previously described [14].…”

Section: Analysis Of Sensitivity Of Mtb H 37 Ra Strains Overproducing Inha and Katgmentioning

confidence: 99%

“…The mode of action was analysed by metabolic labelling of Mtb. H 37 Ra strain with 14 C acetate. Mtb.…”

Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

“…This kind of mutual antibacterial esters of pyrazinoic acid with substituted salicylanilides demonstrated an effective and promising treatment against pathogenic fungi and bacteria (especially against Gram-positive, tuberculous, and atypical mycobacterial strains), including INH-resistant mycobacteria, which are resistant to one or more drugs used clinically [13]. INH-based hydrazone acid amides have also been described as highly active agents against TB [14]. In addition, pyridine-based compounds have been extensively investigated as potential antibacterial, antimycobacterial, antifungal and anticancer drugs [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

et al. 2021

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The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H37Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid.

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Section: Synthesismentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

“…KatG protein encoded by the gene MSMEG_6384 from Mycobacterium smegmatis was overproduced in Mtb. H 37 Ra using pVV16-katG smeg construct previously described [14].…”

Section: Analysis Of Sensitivity Of Mtb H 37 Ra Strains Overproducing Inha and Katgmentioning

confidence: 99%

“…The mode of action was analysed by metabolic labelling of Mtb. H 37 Ra strain with 14 C acetate. Mtb.…”

Section: Investigation Of Mechanism Of Actionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

et al. 2021

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Simple to Complex Amide Derivatives as Potent Anti‐Tuberculosis Agents: A Literature Survey of the Past Decade

Puri

Negi

2022

ChemistrySelect

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Tuberculosis (TB) is a life‐threatening persistent transmittable disease caused by Mycobacterium tuberculosis (MTB) still leftovers one of the most widespread, contagious, and leading deadliest diseases known to mankind all over the world. In recent years, numerous efforts have been made to subjugate the treatment outcomes, and to conquer the drug‐resistant TB (DR‐TB), multidrug‐resistant TB (MDR‐TB), extensively drug‐resistant TB (XDR‐TB), and totally drug‐resistant TB (TDR‐TB) phenomenon. In quest of searching for novel anti‐TB agents, several derivatives containing amide functionality have been synthesized and tested for their anti‐TB activity. It having found that drugs or lead compounds contain amide functionality are privileged motifs that act as primary pharmacophores in many bioactive compounds and possess various biological activities including anti‐tubercular, anti‐inflammatory, anti‐HIV, anti‐malarial, anti‐convulsant, anti‐hypertensive, anti‐diabetic, anti‐depressant, analgesics anti‐cancer, anti‐fungal, anti‐oxidant, anti‐microbial and so on. This review covers the past decade (2010–2022) of advances made towards the breakthrough of anti‐TB agents holding amide functionality. It is hoped that the comprehensive literature survey will be helpful and will open a new avenue in the pursuit for rational designs of more active and less toxic amide functionality‐based anti‐TB drugs.

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Synthesis and Bio‐evaluation of GR135486X Derivatives as Potent Anti‐Tubercular Agents

et al. 2023

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The anilinopyridine derivatives were designed, synthesized and evaluated against Mycobacterium tuberculosis H37Rv. The detail SAR study was carried out using various analogues including positional isomers. The screening data revealed that the free −NH2 on pyridine ring is crucial for antitubercular activity. The current study identified three promising leads 16 e, 16 i and 16 o with MIC 3.1, 3.1 and 1.2 μM, respectively. Important to note that the compound 16 o showed excellent selectivity index of 135.58 when its antitubercular activity was compared with the inhibition of CHO−K1 cells. The other notable compounds were 16 b, 16 d, 16 e, 16 f, 16 g, 16 h, 16 i, 16 l and 16 q which exhibited anti‐TB activity with MIC ≤25 μM. Interestingly, compounds 16 e, 16 i and 16 o did not show inhibition of bacterial pathogen panel indicating the selectivity of this class of compounds towards Mtb. Furthermore, physico‐chemical and ADMET properties of the synthesized derivatives were studied. The compounds fulfill the criteria of Lipinski's rule of five for drug‐likeness.

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Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity

Cited by 15 publications

References 24 publications

Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

Simple to Complex Amide Derivatives as Potent Anti‐Tuberculosis Agents: A Literature Survey of the Past Decade

Synthesis and Bio‐evaluation of GR135486X Derivatives as Potent Anti‐Tubercular Agents

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