03604nas a2200385   4500008004100000022001400041245019700055210006900252260006700321300001200388490000700400520219800407653001002605653001202615653002402627653000902651653002102660653000802681653004902689653002602738653004602764653000902810653002702819653002202846100002302868700002302891700003402914700002502948700002002973700002202993700002403015700002603039700002403065856012903089       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.  uhttps://library.ncl.res.in/content/design-synthesis-structural-characterization-ir-1h-13c-15n-2d-nmr-x-ray-diffraction-and-002428nas a2200301   4500008004100000022001400041245009900055210006900154260006700223300001200290490000700302520136400309653002801673653003301701653001601734653002701750100002101777700002101798700002301819700003401842700001801876700001901894700002201913700002201935700002101957700002401978856012402002       2015                        eng d  a1747-027700aTargeting dormant tuberculosis bacilli: results for molecules with a novel pyrimidone scaffold0 aTargeting dormant tuberculosis bacilli results for molecules wit  a111 RIVER ST, HOBOKEN 07030-5774, NJ USAbWILEY-BLACKWELLcFEB  a201-2070 v853 a<p>Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M.tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach - recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors.</p>10aAntitubercular activity10adormant tuberculosis bacilli10apyrimidones10arecursive partitioning1 aJoshi, Rohit, R.1 aBarchha, Avinash1 aKhedkar, Vijay, M.1 aPissurlenkar, Raghuvir, R. S.1 aSarkar, Sampa1 aSarkar, Dhiman1 aJoshi, Rohini, R.1 aJoshi, Ramesh, A.1 aShah, Anamik, K.1 aCoutinho, Evans, C.  uhttps://library.ncl.res.in/content/targeting-dormant-tuberculosis-bacilli-results-molecules-novel-pyrimidone-scaffold-0