Cytotoxicity and Antimycobacterial Properties of Pyrrolo[1,2-a]quinoline Derivatives: Molecular Target Identification and Molecular Docking Studies (original) (raw)
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Bioorganic & Medicinal Chemistry, 2009
We herein describe the synthesis and antimycobacterial activity of a series of 27 different derivatives of 3-benzyl-6-bromo-2-methoxy-quinolines and amides of 2-[(6-bromo-2-methoxy-quinolin-3-yl)-phenyl-methyl]-malonic acid monomethyl ester. The antimycobacterial activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv for nine consecutive days upon a fixed concentration (6.25 μg/mL) at day one in Bactec assay and compared to untreated TB cell culture as well as one with isoniazide treated counterpart, under identical experimental conditions. The compounds 3, 8, 17 and 18 have shown 92–100% growth inhibition of mycobacterial activity, with minimum inhibitory concentration (MIC) of 6.25 μg/mL. Based on our molecular modelling and docking studies on well-known diarylquinoline antitubercular drug R207910, the presence of phenyl, naphthyl and halogen moieties seem critical. Comparison of docking studies on different stereoisomers of R207910 as well as compounds from our data set, suggests importance of electrostatic interactions. Further structural analysis of docking studies on our compounds suggests attractive starting point to find new lead compounds with potential improvements.Synthesis and biological evaluation of quinoline based compounds against Mycobacterium tuberculosis H37Rv.
Bioorganic & Medicinal Chemistry Letters, 2016
Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values < 3.1 µM and IC 50 values < 1.5 µM in primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand out, showing MIC values of 1.6 µM and IC 50 values of 0.5 and 1.0 µM respectively. Both compounds were the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds 16 and 21 were potent against non-replicating M. Tb. and compound 21 was bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the future development of antimycobacterial agents.
Russian Journal of Bioorganic Chemistry
We have synthesized novel pyrazolo-quinoline analogues (P1-10) in an effort to create newer antitubercular drugs against the rising bacterial resistance. NMR, IR and ESI-MS spectra were utilized to characterize the synthesised compounds. The antitubercular activity of the target compounds was evaluated against Mycobacterium tuberculosis. Six derivatives (P1-6) displayed very significant activity at 1.6 μg/mL concentration and were found to be more active than pyrazinamide standard. Thus, as per the drug susceptibility results the MIC value could be considered between 1.6 and 0.8 μg/mL. In addition, all the synthesised compounds were subjected to molecular docking studies against specific protein, Enoyl acyl carrier protein reductase (InhA) in complex with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB ID: 2NSD. Among all the compounds the most effective compounds were found an Autodock score of 11.6 and 11.2 against 2NSD, respectively. Further, Zebrafish larvae have been used to test the teratogenicity of the synthesised compounds. There were no indications of abnormalities with (P2), (P4), (P5), (P6), and (P10) at 0.5 μM.
Synthesis and anti-tuberculosis activity of 2, 4-disubstituted quinolines
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Synthesis and anti-tuberculosis activity of a new series of 2, 4-disubstituted quinolines have been reported. The most promising compounds have been found to exhibit 99% inhibition at 6.25 µg/mL against drug-sensitive M. tuberculosis H37Rv strain and> 90% inhibition at 12.5 µg/mL against isoniazid resistant TB strain. Keywords: Tuberculosis, ring-substituted quinolines, drug-sensitive TB, drug-resistant TB, multi-drug resistant TB, extreme drug-resistant TB
Selective activity against Mycobacterium tuberculosis of new quinoxaline 1,4-di-N-oxides
Bioorganic & Medicinal Chemistry, 2009
New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 lg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4'-fluoro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 lg/mL and SI >500).
Anti-Mycobacterium tuberculosis Activity of Esters of Quinoxaline 1,4-Di-N-Oxide
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Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-diN oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-diN oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-diN oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds
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Bioorganic & Medicinal Chemistry, 2009
A series of 33 quinoline derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H 37 Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in lg/mL. Compounds 5e and 5f exhibited a significant activity at 6.25 and 3.12 lg/mL, respectively, when compared with first line drugs such as ethambutol and could be a good starting point to develop new lead compounds in the fight against multidrug resistant tuberculosis.
Bioorganic & Medicinal Chemistry, 2009
A new series of 20 quinoline derivatives possessing triazolo, ureido and thioureido substituents have been synthesized and their antimycobacterial properties have been evaluated. Compounds 10, 22 and 24 inhibited Mycobacterium tuberculosis H37Rv up to 96%, 98% and 94% respectively, at a fixed concentration of 6.25 lg/mL. Minimum inhibitory concentration of 3.125 lg/mL was obtained for compound 10 and 24, while for compound 22 it was 6.25 lg/mL. Molecular docking calculations suggest critical hydrogen bonding and electrostatic interactions between polar functional groups (such as quinoline-nitrogen, urea-carbonyl and hydroxyl) of anti-mycobacterial (anti-TB) compounds and amino acids (Arg186 and Glu61) of ATP-synthase of M. tuberculosis, could be the probable reason for observed anti-mycobacterial action.
Journal of Molecular Structure, 2023
A series of novel isatin-ciprofloxacin hybrids inhaling oxime, semicarbazone, and thiosemicarbazone groups with hydrogen bonding capacity were designed, synthesized, and evaluated for their in vitro antitubercular activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug-resistant-TB (MDR-TB). All hybrids endowed with potential activities against the tested MTB H37Rv and MDR-TB strains with minimum inhibitory concentration (MIC) in a range of 0.20 to 128 μg/mL. In particular, the most active hybrid 5e (MIC: 0.20 and 0.5 μg/mL) was four and two times more active than the parent ciprofloxacin (MIC: 0.78 μg/mL) and rifampicin (MIC: 0.39 μg/mL) against MTB H37Rv, and 4->256 times more potent than the three references ciprofloxacin (MIC: 2.0 μg/mL), rifampicin (MIC: 32 μg/mL), and isoniazid (>128 μg/ mL) against MDR-TB. Thus, this kind of hybrids holds great promise as future anti-TB agents against both drug-sensitive and drug-resistant MTB strains infection.