02486nas a2200265   4500008004100000022001400041245010900055210006900164260010600233300001400339490000700353520150900360653002101869653001501890653001801905653001801923653001901941100002201960700002401982700002902006700002302035700002302058700001902081856012002100       2015                        eng d  a0960-894X00aDesign and synthesis of 11 alpha-substituted bile acid derivatives as potential anti-tuberculosis agents0 aDesign and synthesis of 11 alphasubstituted bile acid derivative  aTHE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLANDbPERGAMON-ELSEVIER SCIENCE LTDcOCT  a4185-41900 v253 a<p>We have synthesized a series of novel 11 alpha-triazoyl bile acid derivatives. In addition, we also have synthesized N-alkyl and N-acyl derivatives of C-11 amino bile acid esters. All the compounds were evaluated for the inhibitory activity against Mycobacterium tuberculosis H37Ra (MTB) at 30 mu g/mL level. Four lead compounds (2b, 3, 7 and 8) were further confirmed from their dose dependent effect against MTB. These compounds were found to be active against Dormant and active stage MTB under both in vitro as well as within THP1 host macrophages. The most promising compound 2b showed strong antitubercular activities against MTB under in vitro and ex vivo (IC90 value of similar to 3 mu g/mL) conditions and almost insignificant cytotoxicity up to 100 mu g/mL against THP-1, A549 and PANC-1 human cancer cell lines. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity. Molecular docking studies of these compounds into the active site of DprE1 enzyme revealed a similar binding mode to native ligands in the crystal structure thereby helping to establish a structural basis of inhibition of MTB. The synthesized compounds were analyzed for ADME properties and showed potential to develop good oral drug candidates. Our results clearly indicate the identification of some novel, selective and specific inhibitors against MTB that can be explored further for potential antitubercular drug. (C) 2015 Elsevier Ltd. All rights reserved.</p>10aAntituberculosis10aBile acids10aCycloaddition10aDocking study10aIn silico ADME1 aPore, Vandana, S.1 aDivse, Jaisingh, M.1 aCharolkar, Chaitanya, R.1 aNawale, Laxman, U.1 aKhedkar, Vijay, M.1 aSarkar, Dhiman  uhttps://library.ncl.res.in/content/design-and-synthesis-11-alpha-substituted-bile-acid-derivatives-potential-anti-002332nas a2200241   4500008004100000245010600041210007000147260000800217300001200225490000700237520147700244100002401721700002401745700002901769700002101798700002201819700002601841700002301867700002301890700001901913700002201932856013601954       2017                        eng d00aSynthesis and biological evaluation of new fluconazole β-lactam conjugates linked via 1,2,3-triazole0 aSynthesis and biological evaluation of new fluconazole βlactam c  cFEB  a470-4790 v413 a<p>Novel 1,2,3-triazole-linked β-lactam–fluconazole conjugates 12(a–l) were designed and synthesized. The compounds showed potent antifungal activity against two pathogenic Candida strains; Candida albicans ATCC 24433 and Candida albicans ATCC 10231 with MIC values in the range of 0.0625–2 μg mL−1. Compounds 12h, 12j and 12k showed promising antifungal activity against all the tested fungal pathogens except C. neoformans ATCC 34554 compared to fluconazole. Compound 12j in which the β-lactam ring was formed using para-anisidine and benzaldehyde was found to be more potent than fluconazole against all the fungal strains with an IC50 value of &lt;0.015 μg mL−1 for Candida albicans (ATCC 24433). Mechanistic studies for active compounds revealed that the antifungal action was due to ergosterol inhibition. Compounds 12h and 12j at a concentration of 0.125 μg mL−1 caused 91.5 and 96.8% ergosterol depletion, respectively, compared to fluconazole which at the same concentration caused 49% ergosterol depletion. The molecular docking study revealed that all the fluconazole β-lactam conjugates 12(a–l) could snugly fit into the active site of lanosterol 14α-demethylase (CYP51) with varying degrees of affinities. As anticipated, the binding energy for compound 12j (−58.961 kcal mol−1) was much smaller than that for fluconazole (−52.92 kcal mol−1). The synthesized compounds have therapeutic potential for the control of candidemia.</p>1 aDivse, Jaisingh, M.1 aMhaske, Santosh, B.1 aCharolkar, Chaitanya, R.1 aSant, Duhita, G.1 aTupe, Santosh, G.1 aDeshpande, Mukund, V.1 aKhedkar, Vijay, M.1 aNawale, Laxman, U.1 aSarkar, Dhiman1 aPore, Vandana, S.  uhttps://library.ncl.res.in/content/synthesis-and-biological-evaluation-new-fluconazole-%CE%B2-lactam-conjugates-linked-123-triazole