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Design, Synthesis, Structural Characterization by IR , 1 H, 13 C, 15 N, 2D‐ NMR , X‐Ray Diffraction and Evaluation of a New Class of Phenylaminoacetic Acid Benzylidene Hydrazines as pf ENR Inhibitors
Author(s) -
Samal Ramanuj P.,
Khedkar Vijay M.,
Pissurlenkar Raghuvir R. S.,
Bwalya Angela Gono,
Tasdemir Deniz,
Joshi Ramesh A.,
Rajamohanan P. R.,
Puranik Vedavati G.,
Coutinho Evans C.
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12118
Subject(s) - chemistry , amide , hydrogen bond , heteronuclear single quantum coherence spectroscopy , molecule , stereochemistry , docking (animal) , nuclear magnetic resonance spectroscopy , proton nmr , crystallography , biochemistry , organic chemistry , medicine , nursing
Recent studies have revealed that plasmodial enoyl‐ ACP reductase ( pf ENR , F ab I ), 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, pf ENR 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 pf ENR inhibitors. The search for inhibitors began with a virtual screen of the i R esearch database by molecular docking. Hits obtained from the virtual screen were ranked according to their G lide score. One hit was selected as a lead and modified to improve its binding to pf ENR ; from this, a series of phenylamino acetic acid benzylidene hydrazides were designed and synthesized. These molecules were thoroughly characterized by IR , 1 H , 13 C , 15 N , 2 D ‐ NMR ( COSY , NOESY , 1 H ‐ 13 C , 1 H ‐ 15 N 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 1 H ‐ 13 C and 1 H ‐ 15 H HMBC spectra and was confirmed from the NOESY spectra. The molecules were screened for in vitro activity against recombinant pf ENR enzyme by a spectrophotometric assay. Four molecules, viz . 17, 7, 10, and 12 were found to be active at 7, 8, 10, and 12 μ m concentration, respectively, showing promising pf ENR 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.