Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors

IKK-β inhibitors: An analysis of drug–receptor interaction by using Molecular Docking and Pharmacophore 3D-QSAR approaches

“…Although the class constituted by tetracycle derivatives [16] (Fig. 10) contains the smallest number of structures (only 7), our docking results allowed to predict a binding mode similar to that observed for the thiophenecarboxamide class.…”

“…In this case, however, the tricycle and tetracycle class of compounds were merged together. This choice can be easily explained considering that: (a) the two classes share the same binding mode and strength of interactions with key residues such as Cys99; (b) these inhibitors are derived by a common lead compound [16,17] (BMS-345541, Fig. 1 (4)); (c) the number of tetracycle derivatives is too small to carry out and test a statistically valid Pharmacophore/3D-QSAR model (a model based on too few structures easily leads to over-fitting problems).…”

“…Further SAR studies allowed the identification of BMS-345541 (4) as a highly selective and potent inhibitor; starting from this lead compound, amino derivatives of benzimidazoquinoxaline, benzoimidazoquinoline and benzopyrazoloquinazoline were syn- thesized (5) [16], showing an overall improved activity when compared to the lead compound. However, due to toxicity and solubility problems, novel tricycle inhibitors of IKK-␤ have been designed and synthesized (6) [17], with the aim of improving the activity and selectivity against IKK-␤ and of minimizing sideeffects.In order to investigate the binding modes of each class of IKK-␤ inhibitors, we performed Molecular Modeling studies on the 141 inhibitors as collected in the Binding Database (http://www.bindingdb.org) [18].…”

Chemical biology of inflammatory cytokine signaling

“…38 Further structure-activity relationship studies of BMS-345541 as a structural lead have recently revealed that its tetracycline analogs and imidazo(1,2-a)thieno(3,2-e) pyrazines are more potent IKKb inhibitors. 39,40 As a different approach to the development of IKKb inhibitors, the molecular structure of N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxybenzamide (IMD-0354) was designed by analyzing the binding mode of aspirin to IKKb after the construction of the three-dimensional structure of a kinase domain of IKKb by homology modeling with protein kinase A as a template, and the estimation of the structure of active IKKb by referring to a model of IKK regulation. 41,42 The phase I clinical trial of topical formulation of IMD-0354 for treatment of atopic dermatitis has been successfully completed.…”

IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening

“…In this study we used different scoring functions available in FlexX module. Totally 40(7.40%) active compounds that have IC 50 value ranges from 8 nM to 1500 nM were collected from the literature 2,5,7,9,10,[30][31][32][33][34][35][36][37] and randomly chose 500 (92.60%) ChemDiv 38 GPCR focused library compounds that were used as decoys. FlexX-Pharm was used to define pharmacophore constraints, hinge region Cys99 donor mentioned as an optional constraint.…”