5,5'-Methylenedisalicylic Acid Derivatives as Inhibitors of the Protein Phosphatase CppA in Chlamydia trachomatis.

A structure-based designed library of new 5,5'-methylenedisalicylic acid (MDSA) derivatives were synthesized as a functional core and explored for their antibacterial activity against Chlamydia trachomatis. Various well-established reactions such as amide coupling, basic ester hydrolysis, phosphorylation, sulfonation, acetylation, and hydrogenation reactions were utilized to tune or substitute the carboxylic acid and phenolic groups of MDSA, converting them into amide, ester, phosphoryl, sulfonyl, and acetyl functionalities. Both symmetrical and asymmetrical derivatives were prepared and subsequently tested for mammalian cell cytotoxicity, CppA enzyme inhibition, and the inhibition of infection. Among these, compounds 3, 4, and 10a were identified as the most potent and biologically active inhibitors. Additionally, the docking results against the newly constructed CppA model revealed that MDSA and compounds 2-4 form interactions with different residues such as G42, R166, N167, and R237, supporting the requirement of these interactions for biological activity.