Discovery of novel antileishmanial agents in an attempt to synthesize pentamidine-aplysinopsin hybrid molecule.
In an attempt to synthesize pentamidine-aplysinopsin hybrid molecule 25, a lead molecule 8 (containing Z-configured aplysinopsin moiety) was identified for antileishmanial activity. Optimization of lead 8 provided 24 (containing E-configured aplysinopsin) possessing 10 times more activity and 401-fold less toxicity than the drug pentamidine in cell based assays. Synthesis of 24 was possible, surprisingly, because of two innate reactivities of indole-3-carbaldehyde which provided it in diastereo- and regio-selectively pure form without recourse to the long reaction pathway.
Porwal
Sharad
S
Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow, India.
Chauhan
Shikha S
SS
Chauhan
Prem M S
PM
Shakya
Nishi
N
Verma
Aditya
A
Gupta
Suman
S
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis*; D002460:Cell Line; D055808:Drug Discovery; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry
D000981:Antiprotozoal Agents; D007211:Indoles; C015685:aplysinopsin; D010419:Pentamidine; C012381:indole-3-carbaldehyde; D014364:Tryptophan