Synthesis and evaluation of isosteres of N-methyl indolo[3,2-b]-quinoline (cryptolepine) as new antiinfective agents.
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.
Zhu
Xue Y
XY
Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA.
Mardenborough
Leroy G
LG
Li
Shouming
S
Khan
Abdul
A
Zhang
Wang
W
Fan
Pincheng
P
Jacob
Melissa
M
Khan
Shabana
S
Walker
Larry
L
Ablordeppey
Seth Y
SY
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002522:Chlorocebus aethiops; D005658:Fungi / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007536:Isomerism; D007893:Leishmania donovani / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000470:Alkaloids; D000890:Anti-Infective Agents; D000962:Antimalarials; D000977:Antiparasitic Agents; D007202:Indicators and Reagents; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C024015:cryptolepine