Evaluation of dual potentiality of 2,4,5-trisubstituted oxazole derivatives as aquaporin-4 inhibitors and anti-inflammatory agents in lung cells

Abstract

Inflammation is a multifaceted “second-line” adaptive defense mechanism triggered by exo/endogenous threating stimuli and inter-communicated by various inflammatory key players. Unresolved or dysregulated inflammation in lungs results in manifestation of diseases and leads to irreparable damage. Aquaporins (AQPs) are a ubiquitously expressed superfamily of intrinsic transmembrane water channel proteins that modulate the fluid homeostasis. In addition to their conventional functions, AQPs have clinical relevance to inflammation prevailing under the infectious conditions of various lung diseases and this proclaims them as appropriate biomarkers to be targeted. Hence an endeavor was undertaken to identify potential ligands to target AQP4 for the treatment of lung diseases. Oxazole being a versatile bio-potent core, a series of 2,4,5-trisubstituted oxazoles 3a–j were synthesized by a Lewis acid mediated reaction of aroylmethylidene malonates with nitriles. In silico studies conducted using the protein data bank (PDB) structure 3gd8 for AQP4 revealed that compound 3a would serve as a suitable candidate to inhibit AQP4 in human lung cells (NCI-H460). Further, in vitro studies demonstrated that compound 3a could effectively inhibit AQP4 and inflammatory cytokines in lung cells and hence it may be considered as a viable drug candidate for the treatment of various lung diseases.