Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis

Sahoo, Santosh Kumar; Rani, B. Shobha; Gaikwad, Nikhil Baliram; Ahmad, Mohammad Naiyaz; Kaul, Grace; Shukla, Manjulika; Nanduri, Srinivas; Dasgupta, Arunava; Chopra, Sidharth; Yaddanapudi, Venkata Madhavi

doi:10.1016/j.ejmech.2021.113580

Cited by 18 publications

(19 citation statements)

References 38 publications

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“…The target compounds were synthesized as outlined in Scheme 1. Intermediate anilines 4a – d were synthesized following previously reported literature procedure [15] …”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of 4a – d was carried out by following previously reported literature procedure [15] . Briefly, to an ice‐cold solution of 1.5 equiv.…”

Section: Methodsmentioning

confidence: 99%

“…Intermediate anilines 4a-d were synthesized following previously reported literature procedure. [15] Briefly, substituted acetophenone 1a-c was treated with appropriate diesters of oxalic acid in presence of base sodium tert-butoxide to furnish 2 Meanwhile, by employing well-known Pfitzinger reaction condition, [29 -31] substituted acetophenones/ appropriate ethanones (R 4 -COCH 3 ) and isatin 5 were treated with sodium hydroxide in a mixture of ethanol: water (7 : 1) under reflux to form 2-substituted cinchonic acids 6a-aj. Synthesis of nitro substituted cinchonic acid 6j, 6v was carried out through weak base assisted condensation of isatin and corresponding nitro acetophenone, followed by acid catalyzed cyclization of resultant intermediate as reported in literature.…”

Section: Chemistrymentioning

confidence: 99%

“…As isoxazole amides III , these are reported to escape Mtb efflux machinery [13] . Similarly, 2‐methylbenzothiazole based IV and recently a chalcone linked conjugate V of isoxazole derivatives have shown substantial anti‐TB potential [14,15] . Mechanism of action of isoxazole esters remain unclear despite several hypothesis suggesting prodrug like and pyrazinamide type behavior [16] .…”

Section: Introductionmentioning

confidence: 99%

“…[13] Similarly, 2methylbenzothiazole based IV and recently a chalcone linked conjugate V of isoxazole derivatives have shown substantial anti-TB potential. [14,15] Mechanism of action of isoxazole esters remain unclear despite several hypothesis suggesting prodrug like and pyrazinamide type behavior. [16] On the contrary, quinoline and its derivatives have long been considered as pharmacophores for the design of anti-TB agents as exemplified by fluoroquinolone (FQ) class of antibiotics like ciprofloxacin and moxifloxacin.…”

Section: Introductionmentioning

confidence: 99%

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Exploration of Isoxazole‐Carboxylic Acid Methyl Ester Based 2‐Substituted Quinoline Derivatives as Promising Antitubercular Agents

Sahoo

Ahmad

Kaul

et al. 2022

Chemistry & Biodiversity

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In pursuit of potent anti‐TB agents active against drug resistant tuberculosis (DR‐TB), herein we report synthesis and bio‐evaluation of a new series of isoxazole‐carboxylic acid methyl ester based 2‐substituted quinoline derivatives. Preliminary evaluation indicated selectivity towards Mtb H37Rv, with no inhibition of non‐tubercular mycobacterial (NTM) & bacterial pathogen panel. Out of 36 synthesized compounds, majority exhibited substantial inhibition of Mtb H37Rv (MIC 0.5–8 μg/mL). Cell viability test against Vero cells revealed no significant cytotoxicity. Further, screening against drug resistant strains (DR‐Mtb) found hit compound displaying promising potency (MIC 1–4 μg/mL). Structure optimization of the hit led to the identification of lead compound demonstrating potent inhibition of both drug‐susceptible Mtb (MIC 0.12 μg/mL) and drug‐resistant Mtb (MIC 0.25–0.5 μg/mL) along with a high selectivity index (SI) >80. Taken together, with appreciable selectivity and potent activity, these chemotypes show prospect to be turned into a potential anti‐TB candidate.

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“…The target compounds were synthesized as outlined in Scheme 1. Intermediate anilines 4a – d were synthesized following previously reported literature procedure [15] …”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of 4a – d was carried out by following previously reported literature procedure [15] . Briefly, to an ice‐cold solution of 1.5 equiv.…”

Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploration of Isoxazole‐Carboxylic Acid Methyl Ester Based 2‐Substituted Quinoline Derivatives as Promising Antitubercular Agents

Sahoo

Ahmad

Kaul

et al. 2022

Chemistry & Biodiversity

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Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

et al. 2022

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Tuberculosis (TB) has been the highly contagious airborne disease caused by Mycobacterium tuberculosis and the major leading infectious disease with the higher upsurge of morbidity and mortality. Owing to problems in the current regimen for TB and emergence of drug resistance strains, there is a strong necessity for development of new anti-TB drugs with better efficacy, reduced duration of action, along with improved patient compliance. Towards this, the scaffolds reported in 2021 with anti-tubercular activity such as benzofuran, benzothiazinone, benzimidazoles, indole, piperidine, piperazine, pyrazole, pyridine, pyrimidine, pyrrolidine, quinoxaline, triazole, etc. have been critically reviewed along with their structureactivity relationships, mode of actions with anticipations of intuitions to design the newer anti-mycobacterial scaffolds.The present work provide the organized coverage of diversified scaffolds with anti-tubercular profile reported in 2021 along with the insightful discussion on their merits and demerits. The mode of anti-tubercular action against Mycobacterium tuberculosis strains have been presented keeping in mind the novel drug candidates against drug resistant strains [a] Dr.

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Computational Investigation of Isoxazole‐Based Molecules as Potential Drug‐Resistant Anti‐Tuberculosis H37Rv.

Moukhliss

Koubi

Alaqarbeh³

et al. 2023

ChemistrySelect

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Investigation of new active therapeutic drugs against the emerging drug-resistant Mycobacterium tuberculosis is a current medical and health challenge. Based on previously reported isoxazole-based molecules that have a potent effect against Mycobacterium tuberculosis, computational methods were used in the current study to investigate the effect of isoxazolebased molecules as a potential active drug-resistant drug Mycobacterium tuberculosis H37Rv. Molecular models of isoxazole-based molecules were established by 3D-QSAR study, and different results were interpreted to propose 6 candidate agents more active than the previously reported compounds in the literature. Also, the candidate structures are more active than the therapeutic drug agent Isoniazid (NIH) against Mycobacterium Tuberculosis. Evaluation of the synthetic accessibility coefficient and the Lipinski properties of newly designed agent candidates indicate that these agents meet the criteria of a drug according to the Lipinski and Veber rules because they can be synthesized. In-silico evaluation of ADMETox properties shows satisfactory results for most newly designed agent candidates. According to molecular docking, the drug candidates have a high score with a stable docked pose in the receptor (PDB code: 5v3y) compared to Isoniazid (NIH). The DFT and molecular dynamics study confirmed the previous results of 3D-QSAR and molecular docking models.

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Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis

Cited by 18 publications

References 38 publications

Exploration of Isoxazole‐Carboxylic Acid Methyl Ester Based 2‐Substituted Quinoline Derivatives as Promising Antitubercular Agents

Exploration of Isoxazole‐Carboxylic Acid Methyl Ester Based 2‐Substituted Quinoline Derivatives as Promising Antitubercular Agents

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

Computational Investigation of Isoxazole‐Based Molecules as Potential Drug‐Resistant Anti‐Tuberculosis H37Rv.

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