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.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/pharmacology , Bacteria/drug effects , Cell Line , Cell Survival/drug effects , Chemical Phenomena , Chemistry, Physical , Chlorocebus aethiops , Fungi/drug effects , Humans , Indicators and Reagents , Indole Alkaloids , Isomerism , Leishmania donovani/drug effects , Magnetic Resonance Spectroscopy , Mice , Microbial Sensitivity Tests , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Vero CellsABSTRACT
Several N-substituted quindolines were made to further evaluate the role of N-alkylation on the activity of indoloquinolines as antifungal agents. While N-5 substitution is required for these activities, N-10 alkylation alone leads to inactive products but is tolerated in the presence of N-5 alkyl groups. It was also discovered that bis-quindolines appear to have a more expanded antimicrobial spectrum and lower cytotoxicity than their monomeric counterparts.
Subject(s)
Anti-Infective Agents/chemical synthesis , Quinolines/chemical synthesis , Animals , Anti-Infective Agents/pharmacology , Bacteria/drug effects , Cell Death/drug effects , Inhibitory Concentration 50 , Mitosporic Fungi/drug effects , Plasmodium falciparum/drug effects , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
An attempt to understand the pharmacophore-relevant position of the alcoholic moiety in haloperidol and the contributions of other pharmacophoric elements led to the re-synthesis of its tropane analogue (compound 2). An analysis of the binding data suggests that haloperidol binds to the DA receptors with the OH group in the axial position and the OH group, while not essential for binding, enhances binding especially at the D2 receptor. It also became clear that shortening the butyrophenone chain not only reduces binding affinity at the DA receptors but eliminates subtype selectivity.