Sharad Wakode

Indazole: a medicinally important heterocyclic moiety

This article reveals the various biological activities of the heterocyclic compound, indazole, including anti-inflammatory, antimicrobial, antiHIV, anticancer, hypoglycemic, antiprotozoal, antihypertensive, and other activities. From the observed biological activities of the indazole moiety, it is concluded that the medicinal properties of indazole have to be explored in the near future for the treatment of various pathological conditions.

Synthesis, antimicrobial activity and QSAR studies of new 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazoles

Antimicrobial activity of synthesized 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazole derivatives indicated that 3-(4-chlorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (6) and 3-(4-fluorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (20) were the most active compounds. Further, the results of QSAR studies indicated the importance of topological parameters (2)chi and (2)chi(v) in defining the antimicrobial activity of hexahydroindazoles.

Structural insight into selective phosphodiesterase 4B inhibitors: pharmacophore-based virtual screening, docking, and molecular dynamics simulations

Phosphodiesterase (PDE4) is the predominantly expressing family of PDE enzyme in immune and inflammatory cells. Inhibition of PDE4 has been reported to suppress a diverse spectrum of inflammatory responses both in vitro and in vivo. Many PDE4 inhibitors in development are shown to be efficacious in animal models of various inflammatory disorders, such as asthma, COPD, psoriasis, inflammatory bowel diseases, and rheumatoid arthritis, as well as in clinical trials for asthma and COPD. Therefore, PDE4 might prove as potential therapeutic targets in inflammatory and autoimmune diseases. The PDE4 enzyme family consists of four members (named PDE4A, PDE4B, PDE4C, and PDE4D) that are highly expressed in neutrophils, monocytes, central nervous system, and smooth muscles of the lung. Non-selective PDE4 inhibitors like Rolipram are associated with severe side effects like nausea and emesis. Second-generation PDE4 inhibitors like Roflumilast are reported with improved side effects, but narrow therapeutic window. The behavioral correlation of emesis in mice by deleting PDE4D encoding gene confirmed that inhibition of PDE4D, but not PDE4B is responsible for emetic effect of non-selective PDE inhibitors (Jin, Ding, & Lin, 2012). Therefore, selective PDE4B inhibitors can provide anti-inflammatory efficacy without any side effect. However, conserved active site residues of PDE4B and PDE4D make it difficult to design selective PDE4B inhibitors. In the line of identifying selective PDE4B inhibitors, a combined receptorand ligand-based approach can improve the binding affinity and selectivity of PDE4B inhibition. Thirty-four PDE4B structures are available in RCSB-PDB. Hitherto, no structural classification of available co-crystallized PDE4B inhibitors is reported. An in-depth analysis of available PDE4B-inhibitor complexes may help to find empirical parameters for selective enzyme inhibition. Chen et al. (2010) developed multiple pharmacophore models based on the 18 crystal structures of phosphodiesterase 4 (PDE4) with co-crystal ligand for discovering potential PDE4 inhibitors. Srivani, Usharani, Jemmis, and Sastry (2008) performed the crystal structure analysis of PDE4B and PDE4D which led to find significant variations in the M-loop region, which is the integral part of the active site of PDE4B and PDE4D. Ke (2004) performed the similar crystal structure analysis for PDE4 and PDE5 with respect to the metal binding site. In present study, first we retrieved the information from available PDE4B crystal structures and grouped the crystal ligands in different classes based on chemical scaffolds. We have employed structure and ligand-based dual approach for identifying potential and selective molecules for PDE4B. Structure-based approach presents advantage over ligand-based approach by incorporating spatial distribution of hotspot. At the same time ligandbased approach helps to identify key pharmacophoric features in ligands essential for bioactivity. We combined the chemical features of reported crystal ligands of PDE4B in RCSB PDB data bank and developed ligandbased pharmacophores. Using these queries, SPECS database of commercially available small molecules was screened to find new PDE4B inhibitors. To predict the selectivity in PDE4B over PDE4D, the screened molecules were docked in PDE4B (PDB ID: 3G45) and PDE4D (PDB ID: 3G4G) crystal structures using Glide. The stability of top-scoring ligand in PDE4B active site was confirmed by a 10 ns MD simulations (Figure 1). Our results provided critical insight for designing selective PDE4B inhibitors. This work is organized as follows. The crystal structure analysis, pharmacophore modeling, virtual screening (VS), docking and ADME studies, MD simulation materials, and reproducible methods are provided in next section. Further part includes is the analysis and discussion of crystal structure analysis and pharmacophore

Essential oil of Myrica esculenta Buch. Ham.: composition, antimicrobial and topical anti-inflammatory activities

Hydrodistilled oil obtained from the stem bark of Myrica esculenta Buch. Ham. ex D. Don (yield 0.3%) was analysed by capillary GC and GC-MS. The volatile oil consisted mainly of n-hexadecanol (25.2%), eudesmol acetate (21.9%), palmitic acid (11.6%), cis-β-caryophyllene (8.7%), n-pentadecanol (7.7%) and n-octadecanol (7.6%). The oil was found to be a potential antimicrobial agent against Bacillus pumilus, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger and Saccharomyces cerevisiae. The essential oil exhibited significant topical anti-inflammatory activity compared to standard drug in Swiss albino mice ear.

Antimicrobial activity of essential oil and various extracts of fruits of greater cardamom

Greater cardamom (Amomum subulatum Roxb. Zingiberaceae) commonly known as “Bari ilaichi” is a well known plant used in Ayurvedic and Unani medicine. It has been used for the treatment of various diseases and disorders like gastric ulcer. Therefore antimicrobial activity of petroleum ether, methanol and aqueous extracts from leaves and roots, essential oil and isolated vasicine from A. vasica were tested against various microorganisms. Antimicrobial activity was done by disc diffusion method. The zone of inhibition observed was compared with that of standard drugs, ciprofloxacin and fluconazole. Minimum inhibitory concentration was determined against microorganisms used in the study. The results of this study reveal that methanol extract of fruits of A. subulatum shows remarkable antimicrobial activity against Escherichia coli whereas in case of other microorganisms used it was found inferior to the standard drug used. Methanol extract of rind showed good antimicrobial activity against Staphylococcus aureus. It was found that the essential oil isolated was effective against majority of microorganisms used viz. Bacillus pumilus, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Saccharomyces cerevisiae.

3,4-Disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thiones: Synthesis, Antimicrobial Evaluation and QSAR Investigations Using Hansch Analysis

The 3,4‐disubstituted‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione derivatives were synthesized and characterized by physicochemical and spectral means, and the results of antimicrobial study of these compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans by tube dilution method indicated that 4‐(4‐chlorophenyl)‐3‐(4‐nitrophenylsulfonyl)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione 6 and 4‐(4‐fluorophenyl)‐3‐(4‐nitrophenylsulfonyl)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione 12 were the most potential ones. Further, the QSAR studies by Hansch analysis applied to find out the correlation between physicochemical characteristics of synthesized compounds with antimicrobial activity demonstrated the contribution of electronic parameter, total energy (Te) and the topological parameter (valence second order molecular connectivity index (2χv)). Excellent statistically significant models were developed by Hansch approach (r2 = 0.828–0.898) for the three microorganisms under study. The cross‐validated r2 (q2), which is an indication of the predictive capability of the model for all cases was also very good (q2 = 0.776–0.875).

Pharmacophore generation and atom based 3D-QSAR of quinoline derivatives as selective phosphodiesterase 4B inhibitors

Phosphodiesterase 4B (PDE4B) hydrolyses cyclic adenosine monophosphate (cAMP) and thus regulates its intracellular levels. The enzyme has been proposed as a potential drug target against diseases like inflammation and chronic obstructive pulmonary disease. But use of current PDE4B inhibitors is limited due to dose-dependent nausea and vomiting. Adverse effects associated with current PDE4B inhibitors are possibly results of PDE4D inhibition, a highly similar homolog of PDE4B. Here we considered quinoline analogs and applied ligand-based pharmacophore and atom based 3D-QSAR modeling with structure-based docking and ADME approach. A 5-point pharmacophore model was developed and used to derive a predictive 3D-QSAR model for the studied dataset. The obtained r2 and q2 values were 0.96 and 0.91, respectively. The result suggested that the generated 3D-QSAR model is reliable and can be considered for PDE4B activity prediction. Further, a pharmacophore model was employed for virtual screening to identify potent PDE4B inhibitors. The selective ligands for PDE4B were identified through docking and prime binding energy analysis of ligands in both PDE4B and PDE4D. ADME analysis was performed to confirm the drug ability of the selective ligand. To validate docking results, a molecular dynamics simulation was performed for PDE4B complexed with a top scoring ligand, AQ-390/42425549. AQ-390/42425549-PDE4B interactions reported in MD analysis were consistent with the docking results. All the hit molecules were procured and biologically evaluated for percentage inhibition of PDE4B and PDE4D in in vitro enzymatic assays. Among the total of thirteen molecules that were active against PDE4B, ten were selective with little PDE4D inhibition.

Chemical Composition, Antimicrobial and Topical Anti-inflammatory Activity of Valeriana jatamansi Jones. Essential Oil

Abstract Hydrodistilled oil obtained from the whole plant of Valeriana jatamansi Jones. was analyzed by capillary GC and GC-MS. The volatile oil of the plant consisted mainly of sesquiterpenes viz. carotol (10 %), germacrene B (9.5 %), cis-β-farnesene (8 %), α-humulene (6.8 %) and humulene oxide (6.4 %). The oil was found to be a potential antimicrobial agent against Bacillus pumilus, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. When studied for topical anti-inflammatory activity in Swiss albino mice, the essential oil exhibited significant activity as compared to standard drug.

Chemical Constituents Isolated from Zanthoxylum armatum Stem Bark

Phytochemical investigation of the stem bark of Zanthoxylum armatum led to the isolation of three phytoconstituents characterized as 1-linoleo-2,3-diolein (1), α-amyrin acetate (2), and armatonaphthyl arabinoside (3), which were elucidated using spectroscopic and chromatographic analysis. Among the isolated compounds, armatonaphthyl arabinoside (3) is a new naphthyl glycoside.

Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential

Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC50) of 18.42μM and 19.23μM, respectively. The molecular modeling was performed for all the synthesized compounds. The docking results were found in concordant with the observed animal studies.