Design And Synthesis Of New Delhi Metallo-β-lactamase Inhibitors And Activity Study

New Delhi metallo-β-lactamase (NDM-1) was first discovered from a Swedish patient who was infected by Klebsiella pneumoniae in 2009. NDM-1 positive strain was highly resistant to all antibiotics except tigecycline and colistin, clinical β-lactamase inhibitors (such as sulbactam) have no effect on NDM-1. The gene of NDM-1 is located on plasmids which can transfer into neighbour colony, thus making their rapid dissemination in the world. In less than a month from discovery the first patient, NDM-1 has been founded in dozens of countries. By 2010, there were 13 patients who has been infected by NDM-1 positive strains were found in 10 provinces of China. As a result, NDM-1 has a formidable threat to human health which makes the development of NDM-1 inhibitors becomes imminent.NDM-1 belongs to class B1 metallo-β-lactamase (MBLs) which has 2 zinc ions and 1 water molecule as the active catalytic center, thus blocking 2 zinc ion can inhibit the function of NDM-1. A large number of studies have found that carboxyl, hydroximic acid, thiol and heterocyclic group can coordinate with zinc ion. As a result, our group designed 6 groups 112 compounds with monocyclic β-lactam ring, EDTA, sulbactam, captopril, ebselen and AMA as nuclear parent which have thiol, hydroximic acid and heterocyclic group as substituent group.With the help of computer aided drug design software SYBYL-X 2.0, all designed compounds were docked with NDM-1. Docking results showed that 72 designed compounds have higher score than amoxicillin, which is the ligand of NDM-1 crystal. 3 series of 22 designed compounds including 11 new compounds were synthesized and characterized by NMR and MS. These compounds are (Ⅰ) compounds with a penicillanic acid scaffold; (Ⅱ) compounds contain with sulfurs; (Ⅲ) ebselen and its derivatives.Results of NDM-1 inhibitory activity test indicates that 5 compounds, which are compounds LZ2-1-1, LZ2-1-2, LZ2-3-2, LZ2-3-1 and LZ3-7, show potential inhibitation toward NDM-1. Combined these compounds with amoxicillin (1:1), the MIC of amoxicillin inhibiting NDM-1 positive Escherichia coli decrease by 50%, 50%,50%,75% and 75%. Compound LZ3-7, also known as ebselen, is a hit compound to NDM-1(IC50=19μM). Combined ebselen with amoxicillin or meropenem, the MIC of amoxicillin or meropenem inhibiting NDM-1 positive Escherichia coli decreased to 6.25%.