Chlamydia trachomatis, an obligate intracellular Gram-negative bacterial pathogen that undergoes a biphasic life cycle transitioning between the infectious Elementary Body (EB) and the replicative Reticulate Body (RB), is a major public health concern. Chlamydia trachomatis is the causative agent of most frequently reported sexually transmitted diseases and can lead to infectious blindness, infertility, pneumonia and pelvic inflammatory disease. Studies have shown that Chlamydia encode two Hank’s-type kinases in addition to a type 2C Protein Phosphatase (PP2C; CppA) and appears capable of global protein phosphorylation that regulates the important physiological processes in bacteria including metabolism, development, and virulence. A docking model with 5,5’-methylenedisalicyclic acid (MDSA) has suggested that R166 and N167 are important contact points between the enzyme and the inhibitor (Figure 1), which led us to synthesize new derivatives of MDSA to serve as a novel target for the discovery of more potent drug like inhibitors of CppA. This presentation will focus on the recent advances from my work related to the synthesis of novel derivatives of MDSA to alter the activities of CppA. Our synthetic strategy involves a previously developed single step reaction scheme using methyl salicylate, paraformaldehyde and H2SO4 to prepare methyl protected MDSA that in turn is converted into amide functional group containing MDSA derivatives. Upon confirming purity, the synthesized compounds were biologically evaluated to investigate their role in CppA inhibition both in vitro and in vivo. Among them, 5,5'-methylenebis(N,2-dihydroxybenzamide) is biologically active. Furthermore, phosphoryl analogs of MDSA has also been prepared by using Pd(OAc)2/PPh3 mediated reaction in presence of diisopropylethylamine and diethyl phosphite. Unsymmetrical MDSA derivatives containing methyl ester, carboxylic acid, sulfonic acid and hydroxamic acid residues will also be discussed. Docking results, synthetic route and biological data will be provided to demonstrate the role of small molecules to alter developmental regulations in Chlamydia.

5,5'-methylenedisalicylic acid derivatives as protein phosphatase CppA inhibitors in Chlamydia trachomatis

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