Novel phenylurea-pyridinium derivatives as potent urease inhibitors: Synthesis, in vitro, and in silico studies

Abstract

Urease is known as a virulence factor of some pathogen in the living organism. In this study, a novel series of phenylurea conjugated to different alkyl pyridinium were designed, synthesized, and evaluated as urease inhibitors. The results of in vitro urease inhibition revealed that all derivatives were more potent than standard inhibitors, hydroxyurea (IC50 = 100.0 ± 2.5 μM) and thiourea (IC50 = 23.00 ± 0.84 μM) with IC50 value in the range of 4.08 to 6.20 μM. Kinetic assay of the most potent derivative, 4f, demonstrated a mixed type of inhibition. Docking studies confirmed the complete fitting of the synthesized compounds into the urease active site. According to microbial assay, 4f demonstrated high potency and selectivity against C. neoformans compared to the other tested pathogens. 4f also exhibited IC50 values of 143.42 ± 1.9 and 250.08 ± 5.81 µg/ml to inhibit urease enzyme against C. neoformans and P.vulgaris in the ureolytic assay. Also, in silico drug-likeness study revealed the favorable pharmacokinetic properties of synthesized derivatives. The results underline the potential role of phenylurea-pyridinium hybrids against urease in drug discovery.