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 microg/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.

Scheme I

Preparation of 5-Methyl-11H-indeno[3,2-b]quinolinium Iodide, 2

Scheme 2

Synthesis of Benzothienoquinolinium Iodides and Benzofuroquinolinium Iodide

Scheme 3

N-5 Alkylation of Benzothieno[3,2-b]quinoline.

Scheme V

Synthesis of Benzothieno[3,2-b]pyridinium Iodides 11a–d