AUTHOR=Alam Waqas , Khan Haroon , Saeed Jan Muhammad , Rashid Umer , Abusharha Ali , Daglia Maria 

TITLE=Synthesis, in-vitro inhibition of cyclooxygenases and in silico studies of new isoxazole derivatives

JOURNAL=Frontiers in Chemistry

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1222047

DOI=10.3389/fchem.2023.1222047

ISSN=2296-2646

ABSTRACT=<p>Isoxazole belongs to the class of five-membered heterocyclic compounds. The process of developing new drugs has significantly gained attention due to inadequate pharmacokinetic and safety attributes of the available drugs. This study aimed to design a new diverse array of ten novel isoxazole derivatives via Claisen Schmidt condensation reaction. <italic>In vitro</italic> COX-1/2 anti-inflammatory assay, <italic>in silico</italic> molecular docking of potent compounds, Molecular docking simulation, and SwissADME pharmacokinetic profile were investigated in this research. The <italic>in vitro</italic> COX-1 and COX-2 enzyme inhibitory assay showed that almost all the tested compounds exhibited anti-inflammatory effects whereas <bold>C6</bold>, <bold>C5</bold>, and <bold>C3</bold> were found to be the most potent COX-2 enzyme inhibitors among the tested compounds and are good candidates for selective COX-2 inhibitors. <italic>In silico</italic> molecular docking studies coupled with molecular dynamic simulation has been done to rationalize the time-evolved mode of interaction of selected inhibitor inside the active pockets of target COX-2. The binding orientations and binding energy results also showed the selectivity of compounds towards COX-2. Physicochemical properties, pharmacokinetic profile, lipophilicity, water solubility, drug metabolism, drug-likeness properties, and medicinal chemistry of the synthesized isoxazole derivatives were assessed. The SwissADME (absorption, distribution, metabolism, and excretion) database was used to assess the physicochemical properties and drug-likeness properties of the synthesized isoxazole derivatives. All the compounds were shown high GI absorption except Compound 7 (<bold>C7</bold>). Compound 1 (<bold>C1</bold>) and Compound 2 (<bold>C2</bold>) were found to cross the blood-brain barrier (BBB). Lipinski’s rule of five is not violated by any of the ten synthesized isoxazole derivatives. It was predicted with the SwissADME database that <bold>C2</bold>, <bold>C5</bold>, <bold>C6</bold>, <bold>C7</bold>, and <bold>C8</bold> are potent inhibitors of cytochrome (CYP) subtype CYP-2C19. A subtype of CYP-2C9 was inhibited by <bold>C4</bold> and <bold>C7</bold>. The medicinal chemistry of all the compounds <bold>C1</bold>-<bold>C10</bold> showed no PAIN (Pan assay interference compounds) alerts. The improved gastrointestinal (GI) absorption and BBB permeability of <bold>C1</bold> and <bold>C2</bold> can provide a future prospective for new researchers in the medicinal field to investigate the compounds for the management of chronic diseases. The synthesized isoxazole compounds showed excellent <italic>in vitro</italic> COX-1/2 enzymes anti-inflammatory investigations, <italic>in silico</italic> studies, good physicochemical properties, and improved pharmacokinetic profile which will be further investigated via <italic>in vivo</italic> anti-inflammatory activities. Moreover, to further support our findings of the computational research and <italic>in vitro</italic> studies, an <italic>in-vivo</italic> pharmacokinetic profile is suggested in the future.</p>