Insights into ETA subtype selectivity of benzodiazepine endothelin receptor antagonists by 3D-QSAR approaches

Abstract

ET(A) subtype selective antagonists constitute a novel and potentially important class of agents for the treatment of pulmonary hypertension, heart failure, and other pathological conditions. In this paper, 60 benzodiazepine derivatives displaying potent activities against ET(A) and ET(B) subtypes of endothelin receptor were selected to establish the 3D-QSAR models using CoMFA and CoMSIA approaches. These models show excellent internal predictability and consistency, external validation using test-set 19 compounds yields a good predictive power for antagonistic potency. Statistical parameters of models were obtained with CoMFA-ET(A) (q (2) = 0.787, r (2) = 0.935, r (2) ( pred ) = 0.901), CoMFA-ET(B) (q (2) = 0.842, r (2) = 0.984, r (2) ( pred ) = 0.941), CoMSIA-ET(A) (q (2) = 0.762, r (2) = 0.971, r (2) ( pred ) = 0.958) and CoMSIA-ET(B) (q (2) = 0.771, r (2) = 0.974, r (2) ( pred ) = 0.953) respectively. Field contour maps (CoMFA and CoMSIA) corresponding to the ET(A) and ET(B) subtypes reflects the characteristic similarities and differences between these types. The results of this paper provide valuable information to facilitate structural modifications of the title compounds to increase the inhibitory potency and subtype selectivity of endothelin receptor.

An Efficient Synthetic Approach Towards Benzo[b]pyrano[2,3-e][1,4]diazepines, and Their Cytotoxic Activity

“…The good replaceable active methylthio moiety in compound 5 was cyclized with NH 2 NH 2 •H 2 O, afforded the amino pyrazole derivative 6 with a 65% yield (Scheme 2). Similarly, it was smoothly condensed with hydroxylamine, phenyl hydrazine, thiosemicarbazide, urea, thiourea, and guanidine hydrochloride to provide the target compounds (7)(8)(9)(10)(11)(12). The gesture of the methylthio protons initially observed in compound 5 ( 1 H NMR) at 2.73 ppm was vanished, whereas the NH 2 protons were observed around δ~7.00 ppm.…”

“…Yellow powder (EtOH) with a 65% yield; mp 205-207 ,59.78;H,3.94;N,24.90%. Found: C,59.47;H,3.63;N,isoxazolo [3 ,4 :4,5]pyrano [2,3-e] [1,4]diazepin-4(6H)-one (7). Yellow crystal (EtOH) with a 71% yield; mp 241-243 59.57;H,3.57;N,19.85%.…”

“…Benzodiazepines (BDZ’s) are privileged heteroaromatic molecules and were considered to be the core of an essential class of pharmaceutically active analogues, so, their synthesis is of high value in the subject of medicinal and pharmaceutical chemistry [ 1 , 2 , 3 , 4 ]. 1,4-Benzodiazepines ( Figure 1 ) are used as anti-microbial [ 5 ], in alcohol withdrawal syndrome (AWS) [ 6 ], as endothelin antagonist [ 7 ], hypnotics [ 8 ], anxiolytics [ 9 ], anticonvulsants [ 10 ], muscle relaxants [ 10 ], anticancer drugs [ 11 , 12 ], sedatives [ 13 , 14 ], and antipsychotics [ 15 ]. Recently, benzodiazepines were also recognized to have anti-proliferative [ 16 ], antimicrobial [ 17 ], anti-inflammatory [ 18 ], anti-plateletanti-ulcer [ 19 ], and analgesic [ 20 ].…”

Ortho versus Meta Chlorophenyl-2,3-Benzodiazepine Analogues: Synthesis, Molecular Modeling, and Biological Activity as AMPAR Antagonists

“…The prototypic compound of the 2,3-BDZ family, 7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466; Figure ) was first introduced in the 1980s and has been used as a template and standard in the synthesis and activity evaluations of new GYKI compounds . While the 2,3-BDZs’ structures (Figure ) have different pharmacological activity besides their effect on the central nervous system, they also possess anti-inflammatory, antimicrobial, vasopressin antagonist, endothelia antagonist, cholecystokinin antagonist, antithrombotic, anti-HIV, and antiproliferative activities . Hence, there is a keen interest in 2,3-BDZ for applications in numerous fields besides neurology.…”