Synthesis and Evaluation of Isosteres of N-Methyl Indolo[3, 2-b]-quinoline (Cryptolepine) as New Antiinfective Agents.

Abstract Isosteres of cryptolepine ( 1 ) were synthesized and evaluated for their antiinfective activities. Overall, the sulfur isostere, 5-methyl benzothieno[3,2- b ]quinolinium salt ( 5b ), was equipotent to 1 and has shown no cytotoxicity at 23.8 μg/mL. Compound 5b was also found to have a broad spectrum of activity. Both the carbon and oxygen isosteres were less potent than cryptolepine. A limited library of 2-substituted analogs of 5b has been synthesized and evaluated in antifungal screens but did not show increase in potency compared to the unsubstituted 5b . Similarly, evaluation of tricyclic benzothieno[3,2- b ]pyridines while showing promise in individual screens did not produce an overall increase in potency. Overall, the evaluation of the activities of 5b compared with standard antifungal/anti-protozoal agents suggests that the benzothienoquinoline scaffold could serve as a lead for optimization.