Synthesis and Biological Activity of Piperine Derivatives as Potential PPARγ Agonists.

A series of novel 3-phenyl-1-(alkylphenyl)-9-oxa-4-azaphenanthren-10-ones and (E)-1-phenyl-3-(aryl)prop-2-en-1-ones were synthesized and characterized by IR, 1H NMR, 13C spectroscopy and elemental analysis. The synthesized Compounds 5a–f were subjected to molecular docking simulation with three proteins, namely, tyrosyl-tRNA synthetase, heme oxygenase 1 and acetylcholinesterase to evaluate the antibacterial, antioxidant and acetylcholinesterase inhibition, respectively. Moreover, the docked poses of all compounds inside the proteins were subjected to further dynamic simulation through the calculation of the binding free energy using MM-GBSA analysis. Compound 5d exhibits high potential inhibition against antibacterial, antioxidant and acetylcholinesterase activities. Compounds 3d, 3f, 5a and 5d recorded an important scavenging activity in DPPH and ABTS assays. Investigation of the anti-acetylcholinesterase activity of the synthesized compounds showed that Compounds 5a and 3d are the most potent inhibitors against AchE, with percent inhibition values of 38 and 30%, respectively. Communicated by Ramaswamy H. Sarma

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl(DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50 = 0.042) in comparison to the standard SB203580 (IC50 = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.

Synthesis of novel indolo[3,2-c]isoquinoline derivatives bearing pyrimidine, piperazine rings and their biological evaluation and docking studies against COVID-19 virus main protease

BackgroundPyrazole-furan and pyrazole-pyrrole moiety are among the molecular structures that were found to have an extensive range of applications in the field of medicine and agrochemical due to their wide spectrum of biological activities. These include antimicrobial activity, anti-glaucoma activity, ocular hypertension activity, and antifungal activity.ResultsAn in silico study was carried out on 37 compounds of pyrazole-furan and pyrazole-pyrrole carboxamide derivatives against Sclerotinia sclerotiorum. Using Spartan 14 software, optimization of the compounds was performed at the DFT/B3LYP/6-31G* quantum mechanical method. PaDEL descriptor software was used to calculate the molecular descriptors, and a Generic Function Approximation (GFA) was employed to generate the model. Out of four models generated, model 1 was found to be the optimal and has the following statistical parameters; R2 = 0.83485, R2adj = 0.793563, cross-validated R2 = 0.74037, and external R2 = 0.58479. Molecular docking study was carried out between the antifungal compounds, and the binding site of S. sclerotiorum (PDB CODE 2X2S) in which compound 7 was identified to have the highest binding energy of − 7.5kcal/mol. This compound “7” has a strong affinity with the macromolecular target point of the S. sclerotiorum (2x2s), producing H-bond and as well as the hydrophobic interaction at target point of the amino acid residue. Considering compound 7 as our scaffold, four (4) more potent compounds (7a, 7b, 7c, and 7d) were designed using optimization method of structure-based designed which have the following docking score, − 7.7, − 7.8, − 7.7, and − 7.7kcal/mol.ConclusionStatistical analyses including variance inflation factor (VIF), mean effect (ME), and applicability domain were conducted on the model. Considering an interpretation of the descriptors given in the discussion, the QSAR model provided an idea of ligand-based design while the molecular docking gave an insight on structure-based design of the new compounds with better activity against S. sclerotiorum in which four (4) compounds 7a, 7b, 7c, and 7d were designed and discovered to be of high quality and have greater binding affinity compared to the one obtained from the literature (compound 7).

Alzheimer's disease (AD) and diabetes mellitus (DM) are related to abnormal changes in enzyme activity. While acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the primary targets in the treatment of Alzheimer's disease (AD), α-glucosidase (α-Gly) and α-amylase (α-Amy) enzymes are known for diabetes mellitus (DM). Here, benzenesulfonamide-based thiourea and thiazolidinone derivatives such as AChE, BChE, α-Gly, and α-Amy inhibitors were reported. The results revealed that compounds 1d and 2c showed promising AChE and BChE inhibition effects. Compound 2a was the most potent inhibitor against α-glycosidase and α-amylase, respectively. Molecular docking studies indicated that the lead compounds' binding energy values and molecular interactions were better than that of tacrine and acarbose. The most bioactive compounds may be considered potent leads for further studies.

Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential PPARγ and SUR agonists

Synthesis of novel antipyrine-azole-S-alkyl derivatives antimicrobial activity, molecular docking, and computational studies

New alkyl (cyclohexyl) 2-oxo-1-(prop‑2-yn-1-yl)-1, 2-dihydroquinoline-4-carboxylates: Synthesis, crystal structure, spectroscopic characterization, hirshfeld surface analysis, molecular docking studies and DFT calculations

Design, synthesis of novel (Z)-2-(3-(4-((3-benzyl-2,4-dioxothiazolidin-5-ylidene)methyl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide derivatives: Evaluation of cytotoxic activity and molecular docking studies

Series of 7-(Trifluoromethyl) substituted indolizine 4a-g was synthesized using the one-pot method. Spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, and HRMS were used for the structure confirmation of newly synthesized compounds. These 4a-g compounds were tested for their anti-inflammatory activity. In this study, we identified novel indolizine derivative compounds 4a-g selectively targeting COX-2 enzyme, tumor necrosis factor-α (TNF-α) and, interleukin-6 (IL-6). The in silico docking studies of 4a-g showed that these compounds have a higher affinity for COX-2 enzyme, TNF- α, and IL-6. In silico ADME profile analysis predicts that these compounds have good gastrointestinal tract and blood-brain barrier absorption. Invitro studies showed that compound 4d significantly reduces the level of COX-2 enzymes as compared to indomethacin. Compounds 4e, 4f, and 4a were also found to significantly reduce the level of TNF-α, while compounds 4f, 4g, and 4d, showed a reduction in the level of IL-6 when compared to indomethacin. Compounds 4a, 4d, and 4f also reduces nitric oxide (NO) level, compared to indomethacin. Overall, the current study illustrates significant anti-inflammatory activities of these novel 7-(Trifluoromethyl) substituted indolizine derivatives.

The parent 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-acetohydrazide (4) has twenty-nine compounds. The starting material for their corresponding mono, dipeptides and reactions with active methylene compounds were produced by chemoselective N-alkylation of 4-Benzyl-2H-phthalazin-1-one (2) with ethyl chloroacetate to afford (4-benzyl-1-oxo-1H-phthalazin-2-yl) methyl acetate (3). The ester 3 was hydrazinolyzed to give hydrazide 4, then azide 5 coupled with amino acid ester hydrochloride and/or amines to produce several monopeptides, then the methyl (2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetyl) glycinate (7a) was hydrazinolyzed to produce corresponding hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(2-hydrazineyl-2-oxo ethyl) acetamide (8a). The hydrazide 8a under azide coupling method was coupled with amino acid ester hydrochloride and/or amines to produce several dipeptides, and the hydrazide 8a was also condensed and/or cyclized with several carbonyl compounds. The cytotoxicity of the synthesized compounds was tested using MTT assay, as well as apoptosis-induction through EGFR inhibition. Compounds 11d, 12c and 12d exhibited potent cytotoxic activities with IC50 values of 0.92, 1.89 and 0.57 μM against MDA-MB-231 cells compared to Erlotinib (IC50 = 1.02 μM). Interestingly compound 12d exhibited promising potent EGFR inhibition with an IC50 value 21.4 nM compared to Erlotinib (IC50 = 80 nM). For apoptosis, compound 12d induced apoptosis in MDA-MB-231 cells by 64.4-fold (42.5% compared to 0.66 for the control); hence, this compound may serve as a potential target-oriented anti-breast cancer agent. These results agreed with the molecular docking studies that highlighted the binding disposition of compound 12d towards EGFR protein. Hence, compound 12d may serve as a potential and selective anti-breast cancer agent.

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (3a–3i) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively. To understand the mechanism of action of these compounds (3a–3i) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a, promising leads worthy of further optimisation.

Structure-based design of benzofuran library as P. aeruginosa quorum sensing inhibitors: Synthesis, biological evaluation and molecular docking study.

Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR alpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR alpha wild type and null mice revealed that PPAR alpha regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR alpha agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR alpha, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.

A sequence of novel 2-(4-benzoyl-2-methyl-phenoxy)-N-(3-chloro-2-oxo-4-phenyl-azetidin-1-yl)-acetamide analogues 9(a-n) were synthesized by multistep synthesis. The newly synthesized compounds were well characterized, and their antimicrobial activities were carried out by disc diffusion and broth dilution methods. Further, all the novel series of compounds (9a-n), were tested against a variety of bacterial and fungal strains in comparison to Ketoconazole, Chloramphenicol, and Amoxicillin as standard drugs, respectively. Compounds 9a, 9e, and 9g as a lead molecule demonstrated a good inhibition against tested strains. Further, molecular docking studies have been performed for the potent compounds to check the three-dimensional geometrical view of the ligand binding to the targeted proteins.