Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.     

New developments for the design,synthesis and biological evaluation of potent SARS-CoV 3CLpro inhibitors

A series of trifluoromethyl, benzothiazolyl or thiazolyl ketone-containing peptidic compounds as SARS-CoV 3CL protease inhibitors were developed and their potency was evaluated by in vitro protease inhibitory assays. Three candidates had encouraging results for the development of new anti-SARS compounds.     

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.     

Kinetics of Inhibition of Rabbit Intestine Alkaline Phosphatase by Heteroligand Peroxo Complexes of Vanadium(V) and Tungsten(VI)

The present work was undertaken to examine and compare some biologically important properties of peroxo compounds of V(V) and W(VI) containing biogenic species as ancillary ligand. New anionic peroxovanadate(V) complex of the type Na[VO(O₂)₂(triglycine)]·3H₂O (pV1) and a molecular peroxotungstate(VI) [WO(O₂)₂(triglycine)]·3H₂O (pW1) were synthesized and characterized for the purpose and their stability in solution was ascertained. Studies on kinetics of inhibition of alkaline phosphatase activity by the newly synthesized compounds and series of dipeptide and amino acid containing peroxo complexes of vanadium and tungsten synthesized previously by us viz., Na[VO(O₂)₂(gly-gly)(H₂O)]·H₂O (gly-gly = glycyl-glycine), Na[VO(O₂)₂(asn)]·H₂O (asn = asparagine), Na[VO(O₂)₂(gln)]·H₂O (gln = glutamine), and [WO(O₂)₂(gly-gly)(H₂O)]·3H₂O, revealed that each of these species is a potent mixed-type inhibitor of the enzyme. Significant difference was noted between the peroxovanadium (pV) and peroxotungsten (pW) compounds in terms of their oxidant activity with reduced glutathione.     

Mononuclear and dinuclear peroxotungsten complexes with co-ordinated dipeptides as potent inhibitors of alkaline phosphatase activity

New molecular peroxotungstate(VI) complexes with dipeptides as ancillary ligands of the type, [WO(O(2))(2)(dipeptide)(H(2)O)].3H(2)O, dipeptide = glycyl-glycine or glycyl-leucine, have been synthesized and characterized by elemental analysis, spectral and physico-chemical methods including thermal analysis. The complexes contain side-on bound peroxo groups and a peptide zwitterion bonded to the metal centre unidentately through an O(carboxylate) atom. Investigations on certain biologically important key properties of these compounds and a set of dimeric compounds in analogous co-ligand environment, Na(2)[W(2)O(3)(O(2))(4)(dipeptide)(2)].3H(2)O, dipeptide = glycyl-glycine and glycyl-leucine, reported previously by us revealed interesting features of the compounds. Each of the compounds despite having a 7 co-ordinated metal centre exerts a strong inhibitory effect on alkaline phosphatase activity with a potency higher than that of the free dipeptide, tungstate or peroxotungstate. The compounds exhibit remarkable stability in solutions of acidic as well as physiological pH and are weaker as substrate to the enzyme catalase, compared to H(2)O(2). The mononuclear and dinuclear peroxotungsten compounds are efficient oxidants of reduced glutathione (GSH), a reaction in which only one of the peroxo groups of a diperoxotungsten moiety of the complexes was found to be active.     

Purification and Characterization of Nk‐3FTx: A Three Finger Toxin from the Venom of North East Indian Monocled Cobra

Snake venom three finger toxins (3FTxs) are a non‐enzymatic family of venom proteins abundantly found in elapids. We have purified a 7579.5 ± 0.591 Da 3FTx named as Nk‐3FTx from the venom of Naja kaouthia of North East India origin. The primary structure was determined by a combination of N‐terminal sequencing and electrospray ionization  liquid chromatography‐mass spectrometry/mass spectrometry. Biochemical and biological characterization reveal that it is nontoxic to human cell lines and exhibit mild anticoagulant activity when tested on citrated human plasma. Nk‐3FTx was found to affect the compound action potential (CAP) and nerve conduction velocity of isolated toad sciatic nerve. This is the first report of a non‐conventional 3FTx from Naja kaouthia venom that reduces CAP for its neurotoxic effect. Further studies can be carried out to understand the mechanism of action and to explore its potential therapeutic application.     

Isolation and characterization of intestinal epithelial cells from normal and SIV-infected rhesus macaques

Impairment of intestinal epithelial barriers contributes to the progression of HIV/SIV infection and leads to generalized HIV-induced immune-cell activation during chronic infection. Rhesus macaques are the major animal model for studying HIV pathogenesis. However, detailed characterization of isolated rhesus epithelial cells (ECs) from intestinal tissues is not well defined. It is also not well documented whether isolated ECs had any other cell contaminants from intestinal tissues during the time of processing that might hamper interpretation of EC preparations or cultures. In this study, we identify and characterize ECs based on flow cytometry and immunohistochemistry methods using various enzymatic and mechanical isolation techniques to enrich ECs from intestinal tissues. This study shows that normal healthy ECs differentially express HLA-DR, CD23, CD27, CD90, CD95 and IL-10R markers. Early apoptosis and upregulation of ICAM-1 and HLA-DR in intestinal ECs are thought to be the key features in SIV mediated enteropathy. The data suggest that intestinal ECs might be playing an important role in mucosal immune responses by regulating the expression of different important regulatory and adhesion molecules and their function.