Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

Wang, Apeng; Lv, Kai; Li, Linhu; Liu, Hongtao; Tao, Zeyu; Wang, Bin; Liu, Mingliang; Ma, Chao; Ma, Xican; Han, Bing; Wang, Aoyu; Lu, Yu

doi:10.1016/j.ejmech.2019.06.038

Cited by 34 publications

(21 citation statements)

References 21 publications

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“…Thirty-five (35) compounds were selected from the newly discovered and synthesized series of N-(2-phenoxy) ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) as antitubercular agents (Wang et al 2019). The compound's response against the Mycobacterium tuberculosis (MTB-H37Rv) was measured as minimum inhibitory concentration (MIC) which is the lowest concentration affecting a decrease in fluorescence of greater than 90% relative to the mean of replicate bacterium-only controls in microgram per milliliter (Wang et al 2019). These values were converted into logarithmic MIC values (pMIC) in order to reduce skewness using Eq.…”

Section: Dataset Collection and Optimizationmentioning

confidence: 99%

“…Similarly, in the global tuberculosis report of WHO (2019), data were reported by 202 countries and territories that account for more than 99% of the world's population and estimated number of TB cases (World Health Organization (WHO) 2019). The existence of extensively drug-resistant (XDR) and the evolution of multidrug-resistant (MDR) TB have attracted the attention of drug scientists who are in search of novel anti-tubercular agents with better bioactivities (Wang et al 2019). Researches have shown that imidazo[1,2-a] pyridine-3-carboxamides (IPA) as an anti-tubercular candidate is currently in the second phase of clinical trials, and it was reported to have resilient inhibitory potency or anti-mycobacterial activity (Wang et al 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The existence of extensively drug-resistant (XDR) and the evolution of multidrug-resistant (MDR) TB have attracted the attention of drug scientists who are in search of novel anti-tubercular agents with better bioactivities (Wang et al 2019). Researches have shown that imidazo[1,2-a] pyridine-3-carboxamides (IPA) as an anti-tubercular candidate is currently in the second phase of clinical trials, and it was reported to have resilient inhibitory potency or anti-mycobacterial activity (Wang et al 2019). It was established that the development of more potent compounds with improved bioactivities is very costly and time-consuming (Adeniji et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative structure-activity relationship (QSAR) modelling study of some novel carboxamide series as new anti-tubercular agents

et al. 2020

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Background: QSAR modelling was performed on thirty-five (35) newly discovered compounds of N-(2-phenoxy) ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to predict their biological activities against Mycobacterium tuberculosis (MTB-H37Rv strain) by using some numerical data derived from structural and chemical features (descriptors) of the compounds. Results: At first, the structure of the compounds was accurately drawn and optimized using the Spartan 14 software at DFT level of theory with B3LYP/6-31G** basis set in a vacuum. The diverse chemometric descriptors were computed from the optimized structures using the PaDEL descriptors software, and the division of the dataset into training and test sets was done based on Kennard-Stone's algorithm. Five (5) models were generated from the training set using genetic function approximation, and model 1 was chosen as the best due to its robust internal and external validation metrics (R 2 train = 0.8563, R 2 adjusted = 0.8185, PRESS = 3.5724, average R 2 m (LOO-train) = 0.6751, Q 2 cv = 0.7534, R 2 pred ¼ 0.7543, R 2 test = 0.6993) which passed the model criteria of acceptability. 6-Bromo-N-(2-(4-bromophenoxy) ethyl)-2ethylimidazo[1,2-a] pyridine-3-carboxamide (compound 13) was used as the structural template for the in silico design due to its high pMIC, and it is within the model's chemical space. Conclusion: Based on the information obtained from model 1, six (6) designed compounds with higher antitubercular activity were obtained. Furthermore, the ADME and drug-likeness prediction of the designed molecules showed good pharmacokinetic properties which indicate the application prospect of these compounds as novel MTB-H37Rv inhibitors. This research could help the medicinal chemists and pharmaceutical practitioners in future designing and development of more potent drug candidates.

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Section: Dataset Collection and Optimizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantitative structure-activity relationship (QSAR) modelling study of some novel carboxamide series as new anti-tubercular agents

et al. 2020

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“…Thirty-five compounds were selected from the newly discovered and synthesized series of N-(2-phenoxy) ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) as antitubercular agents [11]. The chemical structure of the compounds were drawn using ChemDraw Ultralevel software V12.0.2 (Table 1), then geometrically optimized using Spartan 14 software at ground state with Density Functional Theory (DFT/B3LYP/6-31G** [12][13][14][15] in a vacuum which is finally saved as Protein Data Bank (PDB) file format [16].…”

Section: Equilibrium Geometry Of Ligands and Protein Structurementioning

confidence: 99%

Virtual molecular docking study of some novel carboxamide series as new anti-tubercular agents

et al. 2020

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A virtual docking simulation study was performed on thirty-five newly discovered compounds of N-(2-phenoxy) ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA), to explore their theoretical binding energy and pose with the active sites of the Mycobacterium tuberculosis target (DNA gyrase). The chemical structures of the compounds were drawn correctly with ChemDraw Ultra software, and then geometrically optimized at DFT level of theory with Spartan 14 software package. Consequently, the docking analysis was carried out using Molegro Virtual Docker (MVD). Five complexes (Complex 5, 24, 25, 33 and 35) with high binding energy were selected to examine their binding pose with the active sites of the protein. The docking results suggested a good MolDock score (≥ -90 kcal/mol) and Protein-Ligand ANT System (PLANTS) score (≥ -60 kcal/mol) which depicted that the compounds can efficiently bind with the active sites of the target. However, compound 5 has the best binding pose with the MolDock score of -140.476 kcal/mol which formed three hydrogen bond interactions with the Gln 538, Ala 531, and Ala 533 amino acid residues. This research gives a firsthand theoretical knowledge to improve the binding efficiency of these compounds with the target.

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“…They display abroad spectrum of bioactivities, making them attractive scaffolds for potential industrial pharmaceutical applications . Many pyridine‐containing compounds display fabulous medicinal potentialities, including hypnotic and sedative, bone calcium regulator, microtubule‐destabilizing, cholesterol and triglyceride regulator, antitubercular, antidiabetic, antihistaminic, anti‐inflammatory, antiproliferative, and anticancer activities . One of the most important pyridine derivatives is nicotinonitrile as a result of its exhibited unique biological and pharmacological properties.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole, pyrazole and/or pyridine ring systems

Abumelha

2020

Journal of Heterocyclic Chem

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A series of novel nicotinonitrile derivatives were synthesized by hybridization with thiazole, pyrazole, and pyridine ring systems using 4‐aminobenzohydrazide as link‐bridge. The synthetic strategy of nicotinonitrile‐thiazole analogues involves cyclization of the precursor N‐phenyl thiosemicarbazide derivative 4 with chloroacetic acid and phenacyl bromide. The reaction of hydrazide 3 with acetylacetone and/or ethyl acetoacetate was applied as a synthetic route for accessing 2‐((4‐(pyrazole‐1‐carbonyl)phenyl)amino)‐nicotinonitrile derivatives 9–10. The 2‐((4‐(4‐thiazolylidene‐pyrazole‐1‐carbonyl)‐phenyl)amino)nicotinonitriles 14–15 were obtained via a nucleophilic addition of pyrazolone 10 to phenyl isothiocyanate followed by cyclization with chloroacetone, phenacyl chloride, and/or ethyl bromoacetate. The 6‐amino‐4‐aryl‐3,5‐dicyano‐2‐oxo‐1‐(4‐substitutedbenzamido)‐pyridines 19 were synthesized by Knoevenagel condensation N′‐(2‐cyanoacetyl)‐benzohydrazide derivative 16 with substituted benzaldehydes followed by heating with malononitrile. All synthesized products were evaluated for their antioxidant potentialities using of 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid) (ABTS) radical cation delcolorization assay. The nicotinonitrile‐thiazole hybrid 6b was found the most promising antioxidant agent with inhibition activity 86.27%.

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Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

Cited by 34 publications

References 21 publications

Quantitative structure-activity relationship (QSAR) modelling study of some novel carboxamide series as new anti-tubercular agents

Quantitative structure-activity relationship (QSAR) modelling study of some novel carboxamide series as new anti-tubercular agents

Virtual molecular docking study of some novel carboxamide series as new anti-tubercular agents

Synthesis and antioxidant assay of new nicotinonitrile analogues clubbed thiazole, pyrazole and/or pyridine ring systems

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