Target-Based Design of Promysalin Analogues Identifies a New Putative Binding Cleft in Succinate Dehydrogenase

Promysalin is a small-molecule natural product that specifically inhibits growth of the Gram-negative pathogen Pseudomonas aeruginosa (PA). This activity holds promise in the treatment of multidrug resistant infections found in immunocompromised patients with chronic illnesses, such as cystic fibrosis. In 2015, our lab completed the first total synthesis; subsequent analogue design and SAR investigation enabled identification of succinate dehydrogenase (Sdh) as the biological target in PA. Herein, we report the target-guided design of new promysalin analogues with varying alkyl chains, one of which is on par with our most potent analogue to date. Computational docking revealed that some analogues have a different orientation in the Sdh binding pocket, placing the terminal carbon proximal to a tryptophan residue. This inspired the design of an extended side chain analogue bearing a terminal phenyl moiety, providing a basis for the design of future analogues.