Synthesis of inhibitors of metallo-β-lactamase (IMP-1)

Abstract

Since their discovery in 1930, -lactam antibiotics have become the standard treatment for bacterial infections. However, many bacteria have now developed resistance to these drugs. Of particular concern is the metallo--lactamases (MBLs), which are a family of di-zinc containing metalloenzymes capable of hydrolyzing a very broad range of common -lactam antibiotics. MBLs are not inhibited by clavulanic acid, a drug commonly co-administered with b-lactam antibiotics as an inhibitor of other serine -lactamases. The aim of the research is to design, dock (computer calculation of an optimum fit of a molecule into an enzyme active site to find a possible docking geometry and energy), synthesize and assay of potent and selective inhibitors of MBLs (IMP-1). Thiol carboxylic acid derivatives are reported as the most common category of MBL (IMP-1) inhibitors. The thiol derivatives below were designed and their predicted interactions within the active site of IMP-1 were investigated with the aid of MolDock modeling software. Consequently, compounds below were synthesized and assayed against IMP-1. These compounds were synthesized in good yields. Their inhibition potencies (Kic values) were determined for MBL (IMP-1) and L-benzyl tyrosine thiol derivative with n=1 was very potent inhibitor with Kic=0.086p0.024 mM. Additionally, L-phenylalanine and tryptophan derivatives with n=1 showed good inhibition as well with the Kic values of 0.25 mM and 0.47 mM respectively. The rest of inhibitors have shown a range of Kic between 1.45 mM to 9.39 mM. In the second project eleven thiol carboxylic acid compounds were designed, docked and synthesized and assayed against IMP-1. These compounds also were synthesized in good yields and showed Kic values between 1.04 mM to 4.77 mM. In the third project, the ZINC Database Library was used for screening virtual compounds against IMP-1. Amongst 10000 compounds, four below compounds were obtained as the highest ranked docking energy of binding to the active site of IMP-1. From the 10,000 compounds used for virtual screening, the four compounds below were ranked by the MolDock modeling software as the best binders within the active site of IMP-1. Due to the commercial availability of cyclohexanoyl chloride, benzoyl chloride and its nitro derivatives, the cyclopropyl, cyclobutyl, cyclopentylcarboxamide substituents of these compounds were replaced with the corresponding benzamide and cyclohexanecarboxamide side groups. Consequently, compounds below were designed and their inhibition activities were measured against IMP-1. None of the compounds show inhibition activity of IMP-1. In the last project, two lead compounds were used for designing of a new project. Twenty-four imidazole compounds were designed, docked, synthesized and assayed against IMP-1. The new compounds showed better inhibition activity than the lead compounds. However, their Kic were not measured as they were not potent inhibitors.