Design, Synthesis, And Structure-activity Relationships Study Of New N-Hydroxyamide Derivatives As Udp-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC) Inhibitors

The metal-dependent deacetylase UDP-3-O-[(R)-3-hydroxymyristoyl]-N- acetylglucosamine deacetylase (LpxC) is an essential enzyme catalyzes the first committed step in lipid A biosynthesis, the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate. Because LpxC is not exploited by existing antibiotics, it is a target for the development of novel antibiotics. Recently, several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different Gram-negative pathogens.All known LpxC inhibitor incorporated a functional group that coordinates tightly to the active-site zinc. In the thesis, we report that inhibitors with a diphenyl-diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. It also shows a general enhancement of potency over CHIR-090 against pathogenic bacterial strains, such as E. coli and P. aeruginosa. We have captured the binding mode of LPC-009 in complex with LpxC enzymes from E. coli, A. aeolicus and P. aeruginosa. Structural comparison of diverse LpxC enzymes in complex with the same LPC-009 inhibitor reveals large, inherent conformational variations of individual LpxC orthologs and unexpected inhibitor flexibility. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale.LPC-011 an amino group para-substituted the distal phenyl ring in LPC-009 enhanced compound solubility in aqueous solution. It shows a general enhancement of antibiotic activity over CHIR-090 against all of the tested bacterial stains. The crystal structures of the E. coli LpxC in complex with para-amine substituted compound LPC-011 and meta-amine substituted compound LPC-012 display identical to that of the E. coli LpxC/LPC-009 complex. LPC-011 due to the para-amine substitution of the distal phenyl group proximity to the F212 of E. coli LpxC, enhances the edge-to-faceπ-πinteraction between the distal phenyl ring of LPC-011 and F212 of E. coli LpxC, resulting in slightly enhanced activity of the para-amine compound LPC-011 over LPC-009 for E. coli.Stereochemistry is an important factor of modern inhibitor design. We show that the R-stereoisomer at the C2 position of the threonyl group is highly detrimental to the antibiotic profile of LPC-011. In contrast, maintaining the chirality at the C3 position of the threonyl group is less important, and compounds with either S- or R-configuration at the C3 position show similar antibiotic activities.In the course of this research, we also investigated the structure-activity relationship of a targeted small molecule library by replacing the threonyl group with other amino acids or amino acids analogs, while keeping the hydroxmate moiety for coordination of the catalytic zinc ion. Our studies have identified dimethyl-hydroxyl compound LPC-037 and dimethyl-amino compounds LPC-040 as two promising compounds that display nearly...