标题：Rational drug design, synthesis, and in vivo biological activity of new indolyl-imidazolone hybrids as potential and safer non-steroidal anti-inflammatory agents
摘要：Graphical abstractDisplay OmittedAbstractObjectivesThe study aimed to synthesize and evaluate the potential anti-inflammatory and analgesic activities of rationally designed hybrid molecules of imidazolone and indole nuclei linked through a methylene bridge.MethodsIndolyl-imidazolone hybrids were synthesized in three simple steps starting from 2-phenyl-1H-indole (1). In the first step, compound1was converted to 2-phenyl-1H-indole-3-carbaldehyde (2) using standard conditions of the Vilsmeier Haack reaction. Benzoyl glycine was reacted with2(step 2) followed by treatment with aromatic/aliphatic amines (step 3) to furnish the indolyl-imidazolone hybrids.In vivoanti-inflammatory and analgesic activity along with ulcerogenicity of the prepared hybrids were evaluated in experimental animals. Molecular properties and pharmacokinetic profile were also predicted using online computational software. Cyclooxygenase-2 (COX-2) enzyme (PDB: 3pgh) was used for molecular docking studies. Indomethacin and aspirin were used as reference compounds for the comparison purpose.ResultsThe percentage inhibition in edema in rats and reduction in frequency of acetic acid induced writhes in mice indicated that two compounds namely 3-(3-Hydroxpropyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl)methylene]-4H-imidazol-4-one (4g) and 3-(2,4-Dinitrophenyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl) methylene]- 4H-imidazol-4-one (4b) could be useful in treating pain and inflammatory conditions. Both the hybrid molecules exhibited better biological spectrum than the standard drug indomethacin. Additionally, both the potent compounds were noted to be less ulcerogenic than indomethacin. Pharmacokinetic profile predicted using ADMETsar and SwissADME cheminformatic software indicated compound4gto be orally bioavailable with high blood brain barrier permeability. However, molecular docking studies revealed that compound4bbinds to COX-2 enzyme more strongly than4gas indicated by a lower binding energy and formation of hydrogen bond interactions with amino acid residues in the binding pocket.ConclusionsIt could be concluded that hybrid compounds4band4gare promising lead candidates and should be further studied to develop compounds for the treatment of inflammatory conditions.
