03603nas a2200385   4500008004100000022001400041245019700055210006900252260006700321300001200388490000700400520219800407653001002605653001202615653002402627653000902651653002102660653000802681653004902689653002602738653004602764653000902810653002702819653002202846100002302868700002302891700003402914700002502948700002002973700002202993700002403015700002603039700002403065856012803089       2013                        eng d  a1747-027700aDesign, synthesis, structural characterization by IR, 1H, 13C, 15N, 2D-NMR, X-ray diffraction and evaluation of a new class of phenylaminoacetic acid benzylidene hydrazines as pfENR inhibitors0 aDesign synthesis structural characterization by IR 1H 13C 15N 2D  a111 RIVER ST, HOBOKEN 07030-5774, NJ USAbWILEY-BLACKWELLcJUN  a715-7290 v813 a<p>Recent studies have revealed that plasmodial enoyl-ACP reductase (pfENR, FabI), one of the crucial enzymes in the plasmodial type II fatty acid synthesis II (FAS II) pathway, is a promising target for liver stage malaria infections. Hence, pfENR inhibitors have the potential to be used as causal malarial prophylactic agents. In this study, we report the design, synthesis, structural characterization and evaluation of a new class of pfENR inhibitors. The search for inhibitors began with a virtual screen of the iResearch database by molecular docking. Hits obtained from the virtual screen were ranked according to their Glide score. One hit was selected as a lead and modified to improve its binding to pfENR; from this, a series of phenylamino acetic acid benzylidene hydrazides were designed and synthesized. These molecules were thoroughly characterized by IR, 1H, 13C, 15N, 2D-NMR (COSY, NOESY, 1H-13C, 1H-15N HSQC and HMBC), and X-ray diffraction. NMR studies revealed the existence of conformational/configurational isomers around the amide and imine functionalities. The major species in DMSO solution is the E, E form, which is in dynamic equilibrium with the Z, E isomer. In the solid state, the molecule has a completely extended conformation and forms helical structures that are stabilized by strong hydrogen bond interactions, forming a helical structure stabilized by N-H...O interactions, a feature unique to this class of compounds. Furthermore, detailed investigation of the NMR spectra indicated the presence of a minor impurity in most compounds. The structure of this impurity was deduced as an imidazoline-4-one derivative based on 1H-13C and 1H-15H HMBC spectra and was confirmed from the NOESY spectra. The molecules were screened for in vitro activity against recombinant pfENR enzyme by a spectrophotometric assay. Four molecules, viz. 17, 7, 10, and 12 were found to be active at 7, 8, 10, and 12m concentration, respectively, showing promising pfENR inhibitory potential. A classification model was derived based on a binary QSAR approach termed recursive partitioning (RP) to highlight structural characteristics that could be tuned to improve activity.</p>10aADMET10adocking10aenoyl-ACP reductase10aFabI10ahydrogen bonding10aNMR10aphenylaminoacetic acid benzylidene hydrazine10aPlasmodium falciparum10aPlasmodium falciparum enoyl-ACP reductase10aQSAR10arecursive partitioning10aX-ray diffraction1 aSamal, Ramanuj, P.1 aKhedkar, Vijay, M.1 aPissurlenkar, Raghuvir, R. S.1 aBwalya, Angela, Gono1 aTasdemir, Deniz1 aJoshi, Ramesh, A.1 aRajamohanan, P., R.1 aPuranik, Vedavati, G.1 aCoutinho, Evans, C.  uhttp://library.ncl.res.in/content/design-synthesis-structural-characterization-ir-1h-13c-15n-2d-nmr-x-ray-diffraction-and-002326nas a2200313   4500008004100000022001400041245010800055210006900163260010600232300001400338490000700352520125400359653001201613653001201625653001801637653001301655653001901668653001701687100001901704700002201723700002001745700001901765700002401784700001501808700001901823700002301842700002101865856012601886       2016                        eng d  a0960-894X00aSynthesis and docking studies of pyrazine-thiazolidinone hybrid scaffold targeting dormant tuberculosis0 aSynthesis and docking studies of pyrazinethiazolidinone hybrid s  aTHE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLANDbPERGAMON-ELSEVIER SCIENCE LTDcMAY  a2224-22280 v263 a<p>The persistence of Mycobacterium tuberculosis (MTB) in dormant stage assists the pathogen to develop resistance against current antimycobactrial drugs. To address this issue, we report herein the synthesis of N-(4-oxo-2 substituted thiazolidin-3yl) pyrazine-2-carbohydrazide derivatives designed by following the molecular hybridization approach using pyrazine and thiazolidenone scaffolds. The compounds were evaluated against MTB H37Ra and Mycobacterium bovis BCG in dormancy model. Most of the compounds had IC50 values in 0.3-1 mu g/ml range. The active compounds were further tested for anti-proliferative activity against THP-1, Panc-1, A549, and MCF-7 cell lines using MTT assay and exhibited no significant cytotoxicity. We also report molecular docking studies using active analogs and MTB Decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1) to rationalize the biological activity and to provide an insight into the probable mechanism of action and binding mode of hybridized structures. The results obtained validate the use of molecular hybridization approach and also suggest that reported compounds can provide a novel pharmacophore to synthesize lead compounds against dormat MTB. (C) 2016 Elsevier Ltd. All rights reserved.</p>10adocking10aDormant10aHybrid design10aPyrazine10aThiazolidenone10atuberculosis1 aChitre, T., S.1 aAsgaonkar, K., D.1 aMiniyar, P., B.1 aDharme, A., B.1 aArkile, Manisha, A.1 aYeware, A.1 aSarkar, Dhiman1 aKhedkar, Vijay, M.1 aJha, Prakash, C.  uhttp://library.ncl.res.in/content/synthesis-and-docking-studies-pyrazine-thiazolidinone-hybrid-scaffold-targeting-dormant