Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Qin, Rongfei; Wang, Pengxu; Wang, Bin; Fu, Ling; Batt, Sarah M.; Besra, Gurdyal S.; Wu, Chong; Wang, Yanan; Huang, Haihong; Lu, Yu; Li, Gang

doi:10.1016/j.ejmech.2022.114145

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…Several of these inhibitors were investigated for cytotoxicity in various human cell lines, including A 5 4 9 , 6 4 , 6 7 , 7 7 , 8 2 , 8 3 H e L a , 3 7 , 3 9 HepG2, 28,56,66,69,72,74,87,88,[90][91][92]109,111 J-774, 111 THP-1, 60 and Vero cell lines. 9,[37][38][39][40][41][42]44,[47][48][49]51,52,54,98,108,113,119 A small negative correlation (r = −0.291, p = 0.011, Figure 4B) was found between the experimental cytotoxicity concentrations (CC 50 ) and MIC, for covalent binders. This observation suggests that even the most effective covalent binders appear to display a safe profile, encouraging the ongoing search for novel inhibitors.…”

Section: With CC 50mentioning

confidence: 99%

“…To investigate the molecular diversity and ADMET properties of the DprE1 inhibitors disclosed in this review, we collected a data set of a total of 1519 structurally diverse molecules by reviewing the literature from the year 2009 to April 2022. − ,− …”

Section: Physicochemical and Admet Properties Of Dpre1 Inhibitorsmentioning

confidence: 99%

“…These results reveal conclusively that antimycobacterial efficacy significantly depends on the inhibition of the flavoenzyme DprE1. Several of these inhibitors were investigated for cytotoxicity in various human cell lines, including A549, ,,,, HeLa, , HepG2, ,,,,,,,,− ,, J-774, THP-1, and Vero cell lines. ,− ,,− ,,,,,,, A small negative correlation ( r = −0.291, p = 0.011, Figure B) was found between the experimental cytotoxicity concentrations (CC 50 ) and MIC, for covalent binders. This observation suggests that even the most effective covalent binders appear to display a safe profile, encouraging the ongoing search for novel inhibitors.…”

Section: Correlations Of Mic With Ic50dpre1 and With Cc50mentioning

confidence: 99%

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Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

2022

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Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) is a critical flavoenzyme in Mycobacterium tuberculosis, catalyzing a vital step in the production of lipoarabinomannan and arabinogalactan, both of which are essential for cell wall biosynthesis. Due to its periplasmic localization, DprE1 is a susceptible target, and several compounds with diverse scaffolds have been discovered that inhibit this enzyme, covalently or noncovalently. We evaluated a total of ∼1519 DprE1 inhibitors disclosed in the literature from 2009 to April 2022 by performing an in-depth analysis of physicochemical descriptors and absorption, distribution, metabolism, excretion, and toxicity (ADMET), to gain new insights into these properties in DprE1 inhibitors. Several molecular properties that should facilitate the design and optimization of future DprE1 inhibitors are described, allowing for the development of improved analogues targeting M. tuberculosis.

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Section: With CC 50mentioning

confidence: 99%

Section: Physicochemical and Admet Properties Of Dpre1 Inhibitorsmentioning

confidence: 99%

Section: Correlations Of Mic With Ic50dpre1 and With Cc50mentioning

confidence: 99%

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Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

2022

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“…All compounds showed excellent inhibition against MTB H37Ra, with values of up to 1.4 μM MIC for intracellular MTB and IC50 of 23.2 μM in J774A1 macrophages and 70.6 μM in HepG2 cells. Likewise, Qin et al [84] developed thieno-benzenesulfonamide derivatives with inhibitory activity against the decaprenylphosphoryl-β-d-riboside 2′-epimerase enzyme, essential for the biogenesis of the Mycobacterium cell wall. The most promising compound showed a MIC of 0.24 μg/mL but resulted in an IC50 in Vero and HepG2 cells of 3.62 and 36.79 μg/mL, respectively.…”

Section: Promising Drug Candidates With Anti-intracellular Mtb Activi...mentioning

confidence: 99%

Advances in Diagnostics and Drug Discovery against Resistant and Latent Tuberculosis Infection

Shleider Carnero Canales,

Marquez Cazorla,

Furtado Torres

et al. 2023

Pharmaceutics

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Latent tuberculosis infection (LTBI) represents a subclinical, asymptomatic mycobacterial state affecting approximately 25% of the global population. The substantial prevalence of LTBI, combined with the risk of progressing to active tuberculosis, underscores its central role in the increasing incidence of tuberculosis (TB). Accurate identification and timely treatment are vital to contain and reduce the spread of the disease, forming a critical component of the global strategy known as “End TB.” This review aims to examine and highlight the most recent scientific evidence related to new diagnostic approaches and emerging therapeutic treatments for LTBI. While prevalent diagnostic methods include the tuberculin skin test (TST) and interferon gamma release assay (IGRA), WHO’s approval of two specific IGRAs for Mycobacterium tuberculosis (MTB) marked a significant advancement. However, the need for a specific test with global application viability has propelled research into diagnostic tests based on molecular diagnostics, pulmonary immunity, epigenetics, metabolomics, and a current focus on next-generation MTB antigen-based skin test (TBST). It is within these emerging methods that the potential for accurate distinction between LTBI and active TB has been demonstrated. Therapeutically, in addition to traditional first-line therapies, anti-LTBI drugs, anti-resistant TB drugs, and innovative candidates in preclinical and clinical stages are being explored. Although the advancements are promising, it is crucial to recognize that further research and clinical evidence are needed to solidify the effectiveness and safety of these new approaches, in addition to ensuring access to new drugs and diagnostic methods across all health centers. The fight against TB is evolving with the development of more precise diagnostic tools that differentiate the various stages of the infection and with more effective and targeted treatments. Once consolidated, current advancements have the potential to transform the prevention and treatment landscape of TB, reinforcing the global mission to eradicate this disease.

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“…Multi-drug resistant (MDR) pathogens have emerged as a major challenge of the 21st century because life-threatening infections are gradually limiting our therapeutic options, especially for debilitated individuals and immunocompromised patients [1,2]. Potential…”

Section: Introductionmentioning

confidence: 99%

Designing Functionally Substituted Pyridine-Carbohydrazides for Potent Antibacterial and Devouring Antifungal Effect on Multidrug Resistant (MDR) Strains

et al. 2022

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The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16–24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains.

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Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Cited by 10 publications

References 26 publications

Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

Advances in Diagnostics and Drug Discovery against Resistant and Latent Tuberculosis Infection

Designing Functionally Substituted Pyridine-Carbohydrazides for Potent Antibacterial and Devouring Antifungal Effect on Multidrug Resistant (MDR) Strains

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