Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole carboxamides that potently inhibit Phospholipase A2 by binding to an allosteric site on the enzyme.

Inflammation-mediated disorders are on the rise and hence, there is an urgent need for the design and synthesis of new anti-inflammatory drugs with higher affinity and specificity for their potential targets. The current study presents an effective and new protocol for the synthesis of thienyl-pyrazoles through 3 + 2 annulations using a recyclable heterogeneous catalyst Amberlyst-15. Chalcones 3(a-g) prepared from 3-methylthiophene-2-carbaldehyde and acetophenones by Claisen-Schmidt approach reacted with semicarbazide hydrochloride 4 in the presence of Amberlyst-15 in acetonitrile at room temperature producing thienyl-pyrazole carboxamides 5(a-h) in good yields. Alternatively, the compounds 5(a-h) were prepared by conventional method using acetic acid (30%) medium. Structures of synthesized new pyrazoles were confirmed by spectral and crystallographic studies. All the new compounds were evaluated for their in vitro inhibition of Phospholipase A2 from Vipera russelli and preliminary studies revealed that, amongst the designed series, compounds 5b, 5c and 5h showed promising inhibition. Further, the compounds exhibited linear mixed-type inhibition behavior for the sPLA2 enzyme indicating that they bind to an allosteric site distinct from either the calcium or substrate binding site on the enzyme. These kinetic conclusions were further validated by macromolecular rigid-body docking whereby compounds 5c and 5h showed binding to distinct pockets on the protein. These findings present a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorders.

Design and environmentally benign synthesis of novel thiophene appended pyrazole analogues as anti-inflammatory and radical scavenging agents: Crystallographic, in silico modeling, docking and SAR characterization.

Oxidative-stress induces inflammatory diseases and infections caused by drug-resistant microbial strains are on the rise necessitating the discovery of novel small-molecules for intervention therapy. The current study presents an effective and new green protocol for the synthesis of thiophene-appended pyrazoles through 3+2 annulations method. Chalcones 3(a-g) were prepared from 5-chloro-2-acetylthiophene and aromatic aldehydes by Claisen-Schmidt approach. The reaction of chalcones 3(a-g) with phenylhydrazine hydrochlorides 4(a-b) in acetic acid (30%) medium and also with freshly prepared citrus extract medium under reflux conditions produced the thiophene appended pyrazoles 5(a-l) in moderate yields. Structures of synthesized new pyrazoles were confirmed by spectral studies, elemental analysis and single crystal X-ray diffraction studies. Further, preliminary assessment of the anti-inflammatory properties of the compounds showed that, amongst the series, compounds 5d, 5e and 5l have excellent anti-inflammatory activities. Further, compounds 5c, 5d, 5g, and 5i exhibited excellent DPPH radical scavenging abilities in comparison with the standard ascorbic acid. Furthermore, using detailed structural modeling and docking efforts, combined with preliminary SAR, we show possible structural and chemical features on both the small-molecules and the protein that might contribute to the binding and inhibition.

Application of Hydrotropic Solubilization in Spectrophotometric Estimation of Lornoxicam from Tablets.

Lornoxicam is a selective cyclooxygenase-1 and cyclooxygenase-2 inhibitor that exhibits anti-inflammatory, analgesic, and antipyretic activities. It is used in osteoarthritis and rheumatoid arthritis; and in treatment of postoperative pain and primary dysmenorrhoea. Lornoxicam is completely insoluble in water but soluble in alkaline solutions. Hydrotropic solubilization is a technique used to increase the aqueous solubility of poorly water-soluble drugs and the present study was aimed at developing a hydrotropic technique to increase the solubility of lornoxicam, using 2 M sodium benzoate as the hydrotropic agent. Beer's law was obeyed in the concentration range of 4-24 µg/mL at 381 nm. The solubility of lornoxicam in distilled water considerably increased with the addition of a hydrotropic agent. The analysis of tablets indicated good correlation between the amounts estimated and label claim. The LOD and LOQ of lornoxicam were found to be 0.34 µg/mL and 1.038 µg/mL, respectively, indicating good sensitivity of the proposed method. The percentage recovery was found to be 99.99%-100.21%. Thus the proposed method is new, simple, environmentally friendly, accurate, and cost effective and can be successfully employed in routine analysis of lornoxicam in tablets.

Development of Orodispersible Tablets of Candesartan Cilexetil- ß -cyclodextrin Complex.

The aim of this study was to investigate the use of inclusion complexation technique employing ß-cyclodextrin in improving the dissolution profile of candesartan cilexetil, a BCS class-II drug, and to formulate the inclusion complex into orodispersible tablets. The inclusion complexes were formed by physical mixing, kneading, coevaporation, and lyophilisation methods. Inclusion complexes were characterized by FTIR, DSC, XRD, NMR, and mass spectral studies. Inclusion complexes prepared using kneading, and lyophilisation techniques in the molar ratio 1 : 5 with ß-cyclodextrin were used for formulating orodispersible tablets by direct compression with different superdisintegrants like croscarmellose sodium, crospovidone, sodium starch glycolate, and low substituted hydroxypropyl cellulose in varying concentrations. The directly compressible powder was evaluated for precompression parameters, and the prepared orodispersible tablets were evaluated for postcompression parameters. Drug-excipient compatibility studies showed no interaction, and characterization proved the formation of inclusion complex. In vitro disintegration time was found to be within 3 minutes, and all the formulations showed complete drug release of 100% within 20 minutes. The optimized formulation was found to be stable after 6 months and showed no significant change in drug content. This work proved ß-cyclodextrins to be effective solubilizing agent in improving the solubility of poorly water soluble drugs.

Design and characterization of double layered mucoadhesive system containing bisphosphonate derivative.

The objective of this study is to evaluate the effect of formulation variables on different evaluation properties such as cumulative percentage release and swelling index in development of two layered buccal mucoadhesive system consisting of a highly water soluble drug risedronate sodium. The mucoadhesive systems were developed with varied concentrations of the polymers (1-2%) using plasticizer/permeation enhancer (25-50% w/w of polymer). Two layered films comprised of risedronate sodium with chitosan (85% deacetylated) and hydroxypropylmethyl cellulose (HPMC 4KM) interpolymer complex of different ratios were prepared by solvent casting method. An impermeable backing membrane of ethyl cellulose was incorporated into the films. The study shows the effect of multipolymeric films on the release of a bisphosphonates derivative. The optimized formulations showed films with uniform drug content (90.91 ± 0.17-105.53% ± 2.15), thickness (0.22 ± 0.01 mm to 0.31 ± 0.06 mm), mucoadhesivity (26 ± 3.61-42.33 ± 2.82 g), and controlled drug release profile up to a period of 10 hours. The films were also studied for swelling index, moisture uptake, viscosity, folding endurance, water vapor transmission rate, and mucoadhesive time.