Novel molecular hybrids of cinnamic acids and guanylhydrazones as potential antitubercular agents

Bairwa, Ranjeet; Kakwani, Manoj D.; Tawari, Nilesh R.; Lalchandani, Jaya; Ray, Mukti Kanta; Rajan, M. G. R.; Degani, Mariam S.

doi:10.1016/j.bmcl.2010.01.031

Cited by 68 publications

(43 citation statements)

References 22 publications

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“…The considerable number of TB patients in our country supports the fact that the use of early pharmacogenetic testing and a comprehensive clinical history may be useful in identifying patients with a high risk of suffering hepatotoxicity. This type of research further supports the use of personalized medicine in the treatment of TB and might be further carried out on the new anti-TB acrylamide-derived drugs [48] because the genotoxicity of this vinyl monomer is known [49].…”

Section: Discussionmentioning

confidence: 55%

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Chamorro

Castagnino

Aidar

et al. 2017

Pharmacogenetics and Genomics

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a Objectives This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires.Patients and methods We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH.Results This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P < 0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P = 0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P = 0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P = 0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P < 0.001).We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy = 0.675 (P = 0.001) and cross-validation consistency = 10/10].Conclusion ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity. Pharmacogenetics and Genomics 00:000-000

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Section: Discussionmentioning

confidence: 55%

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Chamorro

Castagnino

Aidar

et al. 2017

Pharmacogenetics and Genomics

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“…H 37 Rv compared to RIF in both the lungs and spleens of C57BL/6 mice, indicating the potential therapeutic value of 24 in the treatment of mycobacterial infections. In an attempt to find novel compounds active against TB, a series of phenylacrylamides designed by molecular hybridization of trans-cinnamic acids and guanylhydrazones were synthesized and antiTB efficacy were evaluated (Scheme 3) (Bairwa et al, 2010). While cinnamic acids are already known for their antituberculosis efficacy, guanylhydrazones have been shown to have antimicrobial activity including an interesting gram-negative bacterial endotoxin lipopolysaccharide (LPS) sequestering activity (Gadad et al 2000;Wu et al 2009).…”

Section: Cinnamic Amide Derivativesmentioning

confidence: 99%

Cinnamic Derivatives in Tuberculosis

De¹,

Veau²,

Bedos‐Belval³

et al. 2012

Understanding Tuberculosis - New Approaches to Fighting Against Drug Resistance

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“…New designs have been made by molecular hybridization of E-cinamic acid and guanylhydrazones. Based on an empirical analysis of SAR, Bairwa and colleagues determined that electronic and steric parameters have an important role in the activity of these compounds on M. tuberculosis (48, figure 14).They remain the basis of new anti-TB agents (Bairwa et al, 2010).…”

Section: Hydrazides/hydrazones Derivativesmentioning

confidence: 99%

Antitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design

Bocanegra-García¹,

García²,

Palma-Nicolás³

et al. 2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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Novel molecular hybrids of cinnamic acids and guanylhydrazones as potential antitubercular agents

Cited by 68 publications

References 22 publications

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Effect of gene–gene and gene–environment interactions associated with antituberculosis drug-induced hepatotoxicity

Cinnamic Derivatives in Tuberculosis

Antitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design

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