RESUMEN
The escalating severity of the menace posed by bacterial resistance has rendered the existing antibiotics less effective, thus necessitating the discovery of new antibacterial agents. The current study reports the exploration of substituted N-pyridinylaminonaphthols produced by a straightforward, one-pot multicomponent reaction process as antibacterial agents. The synthesized derivatives were assessed in vitro for their antibacterial properties against a panel of bacterial pathogens. The analogs 4b, 4g, 4h, 4i, 4j, 4l, 4r, and 4t exhibited potent inhibitory activity with minimum inhibitory concentration (MIC) values of 1-2 µg/mL. Notably, 4b, 4l, and 4t displayed an excellent selectivity index. Additionally, they were active against the multidrug-resistant bacterial strains, with 4l exhibiting the best activity against methicillin-resistant Staphylococcus aureus and vancomycin resistant staphylococcus aureus with a MIC of 1 µg/mL. 4l showed synergism with gentamycin and showed bactericidal property in a concentration-dependent manner. Furthermore, the molecule 4l inhibited the DNA gyrase supercoiling activity. Absorption, distribution, metabolism, excretion/toxicity parameters and pharmacokinetic properties were assessed via in silico techniques, which elucidate the potential mode of action. These findings demonstrate the potential of the N-pyridinylaminonaphthol derivatives as antibacterial agents against multidrug-resistant S. aureus.
RESUMEN
With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.
Asunto(s)
Antituberculosos , Inhibidores de Anhidrasa Carbónica , Diseño de Fármacos , Hidrazinas , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis , Rodanina , Rodanina/farmacología , Rodanina/síntesis química , Rodanina/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Estructura-Actividad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Antituberculosos/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Humanos , Hidrazinas/farmacología , Hidrazinas/síntesis química , Hidrazinas/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismoRESUMEN
Cyclodextrin complexes loaded with venetoclax for improved solubility and therapeutic efficacy as repurposed drug. The venetoclax-cyclodextrin inclusion complex was prepared using kneading method. Primarily in-silico molecular docking study was performed to examine the possible interaction between venetoclax and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and extensively characterized. The in-vitro studies were performed using A-549 lung epithelial cancer cells. The in-vivo pharmaco-kinetic studies was performed on wistar rats. The aqueous solubility of venetoclax was increased upto 3.16 folds, as compared with pure venetoclax with entrapment efficiency (EE%) was determined 95.44 ± 0.3%. In-vitro cytotoxicity studies were carried on A-549 lung epithelial cancer cells, wherein BCL-2 receptors were highly over-expressed and IC 50 values for venetoclax and venetoclax- HP-ß-CD complex was calculated at 24 and 48 hrs in the order of 1.241 µg/ml, 0.68 µg/ml and 0.757719 µg/ml, 0.6125 µg/mL, respectively. The oral bioavailability was increased 4.03 times compared to the pure drug. The venetoclax-HP-ß-CD inclusion complexes showed the increased aqueous solubility with improved anticancer activities.Communicated by Ramaswamy H. Sarma.
RESUMEN
In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.
Asunto(s)
Antituberculosos , Mycobacterium tuberculosis , Animales , Chlorocebus aethiops , Antituberculosos/farmacología , Urea/farmacología , Células Vero , Relación Estructura-Actividad , Ácidos Carboxílicos/farmacología , Ésteres/farmacología , Tiourea/farmacología , Isoxazoles/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Ever increasing drug resistance has become an impeding threat that continues to hamper effective tackling of otherwise treatable tuberculosis (TB). Such dismal situation necessitates identification and exploration of multitarget acting newer chemotypes with bactericidal efficacy as a priority, that could efficiently hinder uncontrolled spread of TB. In this context, herein we present design, synthesis and bio-evaluation of chalcone tethered bezoxazole-2-amines as promising anti-TB chemotypes. Preliminary screening of 24 compounds revealed initial hits 3,4,5-trimethoxyphenyl and 5-nitrofuran-2-yl derivative exhibiting selective inhibition of Mycobacterium tuberculosis (Mtb) H37Rv. Further, structural optimization of hit compounds generated 12 analogues, amongst which 5-nitrofuran-2-yl derivatives displayed potent inhibition of not only drug-susceptible (DS) Mtb but also clinical isolates of drug-resistant (DR) Mtb strains equipotently. Moreover, cell viability test against Vero cells found these compounds with favourable selectivity. Time kill analysis led to the identification of the lead compound (E)-1-(4-((5-chlorobenzo[d]oxazol-2-yl)amino)phenyl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one, that demonstrated bactericidal killing of Mtb bacilli. Together with acceptable microsomal stability, the lead compound of the series manifested all desirable traits of a promising antitubercular agent.