Insilico structure based drug design approach to find potential hits in ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Tetraacyldisaccharide 4'-kinase (LpxK) is the prime enzyme responsible for the biosynthesis of lipid A. LpxK is a key antibacterial drug target, but it is less exploitation in Pseudomonas aeruginosa and other bacterial species limits its therapeutic use. Pseudomonas aeruginosa is responsible for severe infections like pneumonia and urinary tract infections. The precautionary measures of Pseudomonas aeruginosa infections are decisive as it results in extensive drug resistance, systemic bacteremia, and ventilator-associated pneumonia. The current rational approach highlights exploiting the use of computer-aided drug design approaches to counter Pseudomonas aeruginosa specific LpxK. The various approaches used were exploring the metabolic pathway database (Metacyc), drug target validation using DEG, protein modeling, ligand docking, e-pharmacophore assisted virtual screening, physicochemical and Toxicity profile prediction studies, and molecular simulations in spotting out novel potential hits compounds. The virtual hits which have highly ranked in the study were STOCK4S-16119, STOCK1S -60869, STOCK6S -43621, STOCK6S -3328, and STOCKS-39892 which can act as a scaffold for the establishment of new hits against LpxK and can result in control of Pseudomonas aeruginosa infectivity.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.

New N-phenylacetamide-linked 1,2,3-triazole-tethered coumarin conjugates: Synthesis, bioevaluation, and molecular docking study.

A series of new 1,2,3-triazole-tethered coumarin conjugates linked by N-phenylacetamide was efficiently synthesized via the click chemistry approach in excellent yields. The synthesized conjugates were evaluated for their in vitro antifungal and antioxidant activities. Antifungal activity determination was carried out against fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Cryptococcus neoformans. Compounds 7b, 7d, 7e, 8b and 8e displayed higher potency than the standard drug miconazole, with lower minimum inhibitory concentration values. Also, compound 7a exhibited potential radical scavenging activity as compared with the standard antioxidant butylated hydroxytoluene. In addition, a molecular docking study of the newly synthesized compounds was carried out, and the results showed a good binding mode at the active site of the fungal (C. albicans) P450 cytochrome lanosterol 14α-demethylase enzyme. Furthermore, the synthesized compounds were also tested for ADME properties, and they demonstrated potential as good candidates for oral drugs.

Pharmacoinformatics approaches to identify potential hits against tetraacyldisaccharide 4'-kinase (LpxK) of Pseudomonas aeruginosa.

Pseudomonas aeruginosa infection can cause pneumonia and urinary tract infection and the management of Pseudomonas aeruginosa infection is critical in multidrug resistance, hospital-acquired bacteremia and ventilator-associated pneumonia. The key enzymes of lipid A biosynthesis in Pseudomonas aeruginosa are promising drug targets. However, the enzyme tetraacyldisaccharide 4'-kinase (LpxK) has not been explored as a drug target so far. Several pharmacoinformatics tools such as comparative metabolic pathway analysis (Metacyc), data mining from a database of essential genes (DEG), homology modeling, molecular docking, pharmacophore based virtual screening, ADMET prediction and molecular dynamics simulation were used in identifying novel lead compounds against this target. The top virtual hits STOCK6S-33288, 43621, 39892, 37164 and 35740 may serve as the templates for the design and synthesis of potent LpxK inhibitors in the management of serious Pseudomonas aeruginosa infection.

Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori.

The enzyme pantothenate synthetase panC is one of the potential new antimicrobial drug targets, but it is poorly characterized in H. pylori. H. pylori infection can cause gastric cancer and the management of H. pylori infection is crucial in various gastric ulcers and gastric cancer. The current study describes the use of innovative drug discovery and design approaches like comparative metabolic pathway analysis (Metacyc), exploration of database of essential genes (DEG), homology modelling, pharmacophore based virtual screening, ADMET studies and molecular dynamics simulations in identifying potential lead compounds for the H. pylori specific panC. The top ranked virtual hits STOCK1N-60270, STOCK1N-63040, STOCK1N-44424 and STOCK1N-63231 can act as templates for synthesis of new H. pylori inhibitors and they hold a promise in the management of gastric cancers caused by H. pylori.

Ultrasound Assisted Synthesis of 4-(Benzyloxy)-N-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl) Benzamide as Challenging Anti-Tubercular Scaffold.

A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a⁻j were synthesized in good yield from the key compound 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, called Schiff 's bases 5a⁻j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a⁻j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski's rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a⁻j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.

Ultrasound Promoted Green Synthesis, Docking Study of Indole Spliced Thiadiazole, α-amino Phosphonates as Anticancer Agents and Antityrosinase Agents.

BACKGROUND: Regardless of recent advances in the development of clinically authorized anticancer agents the number of deaths due to cancer is increasing day by day all over the world. The aim of this research work is to synthesis novel anticancer agents. METHOD: In this work, a new series of diethyl ((1H-indole-3-yl)((5-phenyl-1,3,4-thiadiazole-2-yl)amino) methyl)phosphonate derivatives 6(a-j) were designed and synthesized in Ultrasound by green protocol using Kabachnik-Fields reaction. The structures of the synthesized compounds were confirmed by spectral analysis such as elemental analyses, IR, 1H NMR, 13C NMR, 31P NMR and mass spectra. The synthesized compounds 6(a-j) were appraised for their in vitro anticancer activity against human cancer cell lines such as SK-MEL-2 (melanoma), IMR-32 (Neuroblastoma), HT-29(Colon) and also on normal murine embryonic fibroblast NIH/3T3 by Sulforhodamine B (SRB) assay, using Adriamycin as a standard drug. RESULT: The treatment of SK-MEL-2 cancer cells with 6i showed apoptosis and morphological changes like cell shrinkage, cell wall deformation and reduced number of viable cells. The synthesized derivatives were also evaluated for their anti-tyrosinase effect. Nearly all the tested derivatives have been found to be potent tyrosinase inhibitors. CONCLUSION: Nearly all the compounds were tested, the docking study was performed and indicates that the compounds have good binding interactions with tyrosine kinase enzyme. Absorption, Distribution, Metabolism and Elimination (ADME) properties of the synthesized compounds were also analyzed which manifested their potentiality to thrive as good oral drug candidates.

Ionic Liquid-Catalyzed Green Protocol for Multi-Component Synthesis of Dihydropyrano[2,3-c]pyrazoles as Potential Anticancer Scaffolds.

A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a-j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a-j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.

Antileishmanial potential of fused 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiols: Synthesis, biological evaluations and computational studies.

A series of newer 1,2,4-triazole-3-thiol derivatives 5(a-m) and 6(a-i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC50=79.0µM) and 6f (IC50=79.0µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50=490.0µM). Compounds 5b (IC50=13.96µM) and 6b (IC50=13.96µM) showed significant antioxidant activity. After performing molecular docking study and analyzing overall binding modes it was found that the synthesized compounds had potential to inhibit L. donovani pteridine reductase 1 enzyme. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.

Recent advances in multidimensional QSAR (4D-6D): a critical review.

The quantitative structure activity relationship (QSAR) study is the most cited and reliable computational technique used for decades to obtain information about a substituent's physicochemical property and biological activity. There is step-by-step development in the concept of QSAR from 0D to 2D. These models suffer various limitations that led to the development of 3D-QSAR. There are large numbers of literatures available on the utility of 3D-QSAR for drug design. Three-dimensional properties of molecules with non-covalent interactions are served as important tool in the selection of bioactive confirmation of compounds. With this view, 3D-QSAR has been explored with different advancements like COMFA, COMSA, COMMA, etc. Some reports are also available highlighting the limitations of 3D-QSAR. In a way, to overcome the limitations of 3D-QSAR, more advanced QSAR approaches like 4D, 5D and 6D-QSAR have been evolved. Here, in this present review we have focused more on the present and future of more predictive models of QSAR studies. The review highlights the basics of 3D to 6D-QSAR and mainly emphasizes the advantages of one dimension over the other. It covers almost all recent reports of all these multidimensional QSAR approaches which are new paradigms in drug discovery.