Synthesis, Antimicrobial - Cytotoxic Evaluation, and Molecular Docking Studies of Quinolin-2-one Hydrazones Containing Nitrophenyl or Isonicotinoyl/Nicotinoyl Moiety.

By applying the hybrid molecular strategy, in this study, we reported the synthesis of fifteen quinolin-2-one hydrazones containing nitrophenyl or nicotinonyl/isonicotinoyl moiety, followed by in vitro and in silico evaluations of their potential antimicrobial and anticancer activities. In vitro antimicrobial evaluation of the target compounds on seven pathogenic strains, applying the broth microdilution method, revealed that compound 4a demonstrated the most potential antifungal activity against C. albicans (MIC 512 µg.mL-1) and C. krusei (MIC 128 µg.mL-1). In vitro cytotoxic evaluation of the target compounds on three human cancer cell lines, employing the MTT method, suggested that compound 5c exhibited the most potential cytotoxicities against HepG2 (IC50 10.19 µM), A549 (IC50 20.43 µM), and MDA-MB-231 (IC50 16.82 µM) cells. Additionally, molecular docking studies were performed to investigate the binding characteristics of compounds 4a and 5c with fungal lanosterol 14α-demethylase and human topoisomerase I-II, respectively, thereby contributing to the elucidation of their in vitro antifungal and cytotoxic properties. Furthermore, compounds 4a and 5c, via SwissADME prediction, could exhibit favorable physicochemical and pharmacokinetic properties. In conclusion, this study provides valuable insights into the potential of quinolin-2-one hydrazones as promising candidates for the development of novel antimicrobial and anticancer agents in the future.

Identification of efflux pump inhibitors for Pseudomonas aeruginosa MexAB-OprM via ligand-based pharmacophores, 2D-QSAR, molecular docking, and molecular dynamics approaches.

Efflux pumps have been reported as one of the significant mechanisms by which bacteria evade the effects of multiple antibiotics. The tripartite efflux pump MexAB-OprM in Pseudomonas aeruginosa is one of the most significant multidrug efflux systems due to its broad resistance to antibiotics such as chloramphenicol, fluoroquinolones, lipophilic ß-lactam antibiotics, nalidixic acid, novobiocin, rifampicin, and tetracycline. A promising strategy to overcome this resistance mechanism is to combine antibiotics with efflux pump inhibitors (EPIs), which can increase their intracellular concentration to enhance their biological activities. Based on 143 EPIs with chemically diverse skeletons, the 3D pharmacophore and 2D-QSAR modelings were developed and used for the virtual screening on 9.2 million compounds including ZINC15, DrugBank, and Traditional Chinese Medicine databases to identify new EPIs. The molecular docking was also performed to evaluate the binding affinity of potential EPIs to the distal-binding pocket of MexB and resulted in 611 potential EPIs. The structure-activity relationship analyses suggested that nitrogen heterocyclic compounds, piperazine and pyridine scaffolds, and amide derivatives are the most favorable chemically features for MexAB inhibitory activities. The results from molecular dynamics analysis in 100 ns indicated that ZINC009296881 and ZINC009200074 were the most potential MexB inhibitors with strong binding affinity to the distal pocket and MM/GBSA ∆Gbind values of - 38.97 and - 30.19 kcal mol-1, respectively. The predicted pharmacokinetic properties and toxicity of these compounds indicated their potential oral drugs. Multistep virtual screening of EPIs for MexAB-OprM, efflux pump multidrug resistant of P. aeruginosa.

Flow sensing in developing Xenopus laevis is disrupted by visual cues and ototoxin exposure.

We explored how lateral line cues interact with visual cues to mediate flow sensing behaviors in the nocturnal developing frog, Xenopus laevis, by exposing animals to current flows under different lighting conditions and after exposure to the ototoxin gentamicin. Under dark conditions, Xenopus tadpoles move downstream at the onset of current flow, then turn, and orient toward the direction of the flow with high accuracy. Postmetamorphic froglets also exhibit positive rheotaxis but with less accuracy and longer latency. The addition of discrete light cues to an otherwise dark environment disrupts rheotaxis and positioning. Orientation is less accurate, latency to orient is longer, and animals do not move as far downstream in the presence of light. Compared with untreated tadpoles tested in the dark, tadpoles exposed to gentamicin show less accurate rheotaxis with longer latency and do not move as far downstream in response to flow. These effects are compounded by the presence of light cues. The disruptive effects of light on flow sensing in Xenopus emphasize the disturbances to natural behaviors that may be produced by anthropogenic illumination in nocturnal habitats.

Discovery of AcrAB-TolC pump inhibitors: Virtual screening and molecular dynamics simulation approach.

AcrAB-TolC tripartite efflux pump, which belongs to the RND superfamily, is a main multi-drug efflux system of Escherichia coli (E. coli) because of the broad resistance on various antibiotics. With the discovering of efflux pump inhibitors (EPIs), a combination between these and antibiotics is one of the most promising therapies. Therefore, building a virtual screening model with prediction capacities for the efflux pump inhibitory activities of candidates from DrugBank and ZINC15 dataset, is one of the key goals of this project. Based on the database of 170 diverse chemical structures collected from 28 research journals, two 2D-QSAR models and a 3D-pharmacophore model have been performed. On the AcrB protein (PDB 4DX7), two binding sites have been discovered that match to the hydrophobic trap in the distal pocket and the switch loop in the proximal pocket. After virtual screening processes, twenty candidate AcrAB-TolC inhibitors have been subjected to molecular dynamics simulations, binding free energy calculations and ADMET predictions. The results indicate that three compounds namely DB09233, DB02581, and DB15224 are potential inhibitors with ΔGbind of -42.30 ± 4.58, -40.76 ± 7.30 and -31.06 ± 7.63 kcal.mol-1, respectively.Communicated by Ramaswamy H. Sarma.

Computational assessment and in vitro test of phytochemicals of Usnea aciculifera as potential inhibitors of Escherichia coli efflux pump AcrB.

Lichens produce secondary metabolites that have many pharmaceutical activities such as antimicrobial, antioxidant, antiviral, anticancer, antigenotoxic, anti-inflammatory, analgesic and antipyretic activities. However, there is limited research on their efflux pump inhibitory activities. Twelve phytochemicals were isolated from Usnea aciculifera, and their activity of AcrAB-TolC efflux pump inhibition was evaluated. Four potential compounds, which are diffractaic acid (2), 8' -O- methylstictic acid (5), 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2,4-dimethoxy-3,6-dimethylbenzoate (8) and 3-hydroxy-4-(methoxycarbonyl)-2,5-dimethylphenyl 2-hydroxy-4-methoxy-3,6-dimethylbenzoate (9), were found by virtual screening using pharmacophore and 2D-QSAR model. Compound 8 exhibited AcrB inhibition activity in vitro with an accumulation H33342 percentage compared with untreated control of 202% at a concentration of 50 µM and increased the antibacterial activity of levofloxacin by four-fold at a concentration of 200 µM. By molecular docking and molecular dynamics (MD) simulation, the binding affinity of depside and depsidone derivatives to AcrB was also clarified. Despite the poor docking score to the AcrB binding site, compound 8 was the most stable among the four complexes at 20 ns of MD simulation. The analysis of long MD at 100 ns indicated that compound 8 interacts strongly with the residues in the distal pocket, creating a stable complex with ΔGbind of -31.51 kcal.mol-1. According to the ADMETlab 2.0 web server's predictions of pharmacokinetics and toxicities, compound 8 has the potential for drug development.Communicated by Ramaswamy H. Sarma.