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Anti-tubercular agents. Part 6: Synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones
No full textAs a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a newclass of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6aef,7aed, 9aec and 11aec) molecules against Mycobacterium tuberculosis H37Rv by using rifampicin and linezolide as positive controls is discussed, compounds 7c and 9aec are found to be the most active members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9aec) was
evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that compounds 7c and 9a mayserve as promising lead scaffolds for further generation of newas anti-TB agents
Possible role of macrophages induced by an irridoid glycoside (RLJ-NE-299A) in host defense mechanism
No full textIn order to explore the possible role of macrophages and other necessary immune competent (T and B) cells in
the modulation of immune responses, an attempt was made to study the immunomodulatory effect of an irridoid glycoside (RLJ-NE-299A) isolated from the roots of Picrorhiza kurroa. Both in vitro and in vivo studies were used to evaluate the effect of RLJ-NE-299A on humoral, cellular, and phagocytic activity of macrophages.The data obtained in the present study showed that RLJ-NE-299A significantly increased sheep red blood cell(SRBC) and induced antibody (IgM and IgG) titer and delayed type hypersensitivity (DTH) reaction in mice.Besides augmenting the humoral and cell-mediated immune response, it induced macrophage phagocytosis
and stimulated cytokine-induced macrophage activation and nitric oxide (NO) production, which resulted in a high degree of protection against Candida albicans and Salmonella typhimurium infections. Flow cytometric
analysis indicated the enhanced expression of co-stimulatory surface molecules CD80 and CD86. The ability of RLJ-NE-299A to upregulate these cell surface antigens involved in antigen presentation may provide an
explanation for the increased T-cell mediated immunity involving macrophages. Taken together this in vitro and in vivo preclinical data suggests that RLJ-NE-299A acts as an effective immunomodulator specifically to improve macrophage function during infections. The effects of this agent on these cells at concentrations relevant to in vivo therapy support its immunopharmacologic application to modify cellular immunity
Ring A structural modified derivatives of withaferin A and the evaluation of their cytotoxic potential
No full textRegio-/stereoselective Michael addition to ring A of withaferin-A was performed using an optimized reaction procedure to synthesise a library of 2,3-dihydro,3-�-substituted withaferin-A derivatives. The analogues thus obtained were evaluated for in vitro cytotoxicity against various human cancer cell lines.3-Azido analogue exhibited 35-fold increase (IC50 = 0.02–1.9 �M) in cytotoxicity against almost the entire cell lines tested when compared to the parent molecule. However, further modifications of 3-azido analogue with various alkynes under Husigen’s cycloaddition conditions generated a variety of triazole
derivatives with reduced cytotoxicity
Ten marker compounds-based comparative study of green tea and guava leaf by HPTLC densitometry methods: Antioxidant activity profiling
No full textHigh-performance thin layer chromatography (HPTLC) method for the separation and quantitative determination of ten markers (catechins, flavonoids, and phenolics) in
different extracts of green tea and guava leaf has been developed and the antioxidant activity profiles of the two plant extracts have been determined. Ten marker compounds
have been resolved using silica gel 60 F254 plates, toluene/acetone/formic acid (5:4:1 v/v/v)for markers 1–6, and toluene/ethyl acetate/formic acid/methanol (3:3:0.8:0.2 v/v/v/v) for markers 7–10 as the mobile phases. The high-performance thin layer chromatography densitometry was performed at wavelengths of 282 and 285 nm for the markers 1–6 and 7–10, respectively. Potent antioxidant activity and the presence of phenolics and flavan-3-ols has been observed for the guava leaf extracts suggestive of its use as an alternate economical source of antioxidants over green tea – the well-established food additive/
nutraceutical agent
A comparative study of proapoptotic potential of cyano analogues of boswellic acid and 11-keto-boswellic acid
No full textSemi-synthetic analogues of b-boswellic acid (BA) and 11-keto-b-boswellic acid (KBA) were comparatively
evaluated for in vitro cytotoxicity against human myeloid leukaemia (HL-60) and human cervical carcinoma (HeLa) cells. 2-Cyano analogues of both the triterpenes were observed to have significant cytotoxicity against both the cells, displaying cytotoxicity in HL-60 cells at low concentrations. Further investigations suggested the proapoptotic potential associated with the two molecules to induce cytotoxicity in HL-60 cells, where one of them showed early proapoptotic effect as evidenced by several
biological end-points of the apoptosis such as annexinV binding, DNA fragmentation and increase in sub-G0 DNA fraction and apoptotic bodies formation (Hoechst 33258 staining and SEM studies)
A propionyloxy derivative of 11-keto-β-boswellic acid induces apoptosis in HL-60 cells mediated through topoisomerase I & II inhibition
No full textBoswellic acids have invariably been reported for their antiproliferative potential in various cell systems.
In the present study the growth inhibitory effect of propionyloxy derivative of 11-keto-�-boswellic acid
(PKBA; a semisynthetic analogue of 11-keto-�-boswellic acid) on HL-60 promyelocytic leukemia cells is being reported for the first time. In the preliminary studies, in vitro cytotoxicity of PKBA was investigated against eight human cancer cell lines viz., IMR-32, SF-295 (both neuroblastoma), PC-3 (prostate), Colo-205 (colon), MCF-7 (breast), OVCAR-5 (ovary), HL-60, Molt-4 (both leukemia) and their respective IC50 values were found to be 5.95, 7.11, 15.2, 14.5, 15, 15.9, 8.7 & 9.5�g/ml, respectively. For determining the mechanism of cell death in HL-60 cells, PKBA was subjected to different mechanistic studies. DNA
relaxation assay of PKBA revealed inhibition of both topoisomerases I & II. The fragmentation analysis of
DNA revealed typical ladders indicating the cytotoxic effect to be mediated by induction of apoptosis. The
morphologic studies of PKBA showed the presence of true apoptotic bodies. Apoptosis was confirmed further by flow-cytometric detection of sub-G1 peaks and enhanced annexin-V-FITC binding of the cells.The activation of apoptotic cascade by PKBA in HL-60 cells was found to be associated with the loss of mitochondrial membrane potential, release of cytochrome c, activation of initiator and executioner caspases and cleavage of poly ADP ribose polymerase (PARP). In vivo studies of PKBA revealed antitumoral activity against both ascitic and solid murine tumor models. These studies thus demonstrate PKBA to induce apoptosis in HL-60 cells due to the inhibition of topoisomerases I and II
Entrapment and Kinetic Resolution of Stabilized Axial and Equatorial Conformers of Spiro-β-lactams
No full textThe facile synthesis of the stabilized axial and
equatorial conformers of spiro-β-lactams was achieved via
entrapment of cyclohexanone imines (Schiff bases) with acetoxyacetyl chloride in a [2 + 2]-cycloaddition reaction followed by their kinetic resolution. The immobilization of the racemic substrates on an inert solid support significantly reduced the reaction time and improved the enantioselectivity of conformers during kinetic resolution. The mechanism of the formation of the spiro-β-lactams was explored using B3LYP/6-31+G* level quantum chemical calculation
Identification of Mycobacterium tuberculosis genes preferentially expressed during human infection
No full textThe identification of Mycobacterium tuberculosis genes, specifically expressed during infection is a key
step in understanding molecular mechanism of mycobacterial pathogenesis. Such genes likely encode proteins required for mycobacterium’s survival and progressive infection within the host. In this study,we applied in-vivo-induced antigen technology (IVIAT) to M. tuberculosis and identified 11 putative in-vivo induced genes encoding for immunogenic proteins of diverse functions; these included transcriptional regulators (Rv1460 and Rv2565), biosynthesis and macromolecule metabolism (leuD, guaB1,
plcC, hupB and glyS), polyketide synthases (pks6 and pks9), cell processes (ctpA) and one with unknown function (Rv3701c). Quantitative real time-PCR analysis of these genes in the specimens obtained from TB patients demonstrated induced expression of eight genes as compared with bacteria grown in-vitro. In addition, distribution of these genes in different strains of M. tuberculosis was analyzed using PCR and their nucleotide sequence alignments and they were found to be widely distributed among M. tuberculosis isolates including multiple-drug resistant (MDR) and extensively-drug resistant (XDR). This study
identified several antigenic determinants of M.tuberculosis expressed during infection, which might help pathogens adapt to or counter hostile environments and suggesting their role during disease process
A rational approach for the design and synthesis of 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles as a new class of potential non-purine xanthine oxidase inhibitors
No full textXanthine oxidase is a complex molybdoflavoprotein that catalyses the hydroxylation of xanthine to uric
acid. Fifty three analogues of 1-acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles were rationally designed and
synthesized and evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Some notions
about structure activity relationships are presented. Six compounds 41, 42, 44, 46, 55 and 59 were found to be most active against XO with IC50 ranging from 5.3 lM to 15.2 lM. The compound 59 emerged as the most potent XO inhibitor (IC50 = 5.3 lM). Some of the important interactions of 59 with the amino acid residues of active site of XO have been figured out by molecular modeling
Podophyllum lignans array of Podophyllum hexandrum Royle populations from semi-desert alpine region of Zanskar valley in Himalayas
No full textPodophyllum hexandrum Royle (Syn. P. emodi Wale) a perennial rhizomatous herb found in alpine region
distributed in the entire range of Himalayas from Ladakh to Sikkim at an altitude of 3000–4200masl is an preferred commercial source of Podophyllum lignans. It contains three times more Podophyllotoxin than the American species, Podophyllum peltatum. The present study was aimed to investigate variation of Podophyllum lignans contents based on six marker compounds viz. Podophyllotoxin; Deoxypodophyllotoxin;Picropodophyllotoxin; Podophyllotoxin �-d-glucopyanoside; Isopicropodophyllone; 4�-Demethyldeoxypodophyllotoxin, �-d-lucopyanoside, in P. hexandrum population growing at three locations. Further, ontogenetic and morphogenetic variations of Podophyllum lignan contents were studied to investigate dynamics of accumulation of these compounds. Representative collections from three locations viz., Panikhar, Padam and Tangoli located in Trans Himalayan semi-desert region of Zanskar
valley were harvested at three stages (dormancy, active growth and maturity). Plants were dissected into
root, rhizome and rhizome-buds, dried separately and assayed for Podophyllum lignan contents by high
performance liquid chromatography