Scientists at National Chemical Laboratory (CSIR-NCL), Pune have achieved the first total synthesis of flinderoles. Recently, flinderoles, the type of Indole alkaloids, isolated from Australian plants have showed promising antimalarial activities.
Scientists around the world continuously look for new chemical compounds to combat malaria as antimalarial drug resistance is a major public health problem and hinders the control of the disease.
Finderoles are new addition to the list of natural products for treating malaria, earlier plant-based products being quinine, artemisinin etc. and their derivatives.
Malaria, one of the deadly diseases, infected about 225 million people worldwide in 2009 with an estimated 780,000 deaths; out of these 90 per cent occurred in Africa and 85 per cent are children under the age of five.
All natural products are not totally synthesized. Total syntheses of natural products pose challenges to the scientific community because of their complex structures. Once synthesized, it becomes possible to go for several structural analogues as many-a-time derivatives have shown potent activity than the parent compound. Synthesizing natural product in the lab also saves the cutting of trees.
Earlier, scientists from Australia isolated the indole alkaloids, flinderoles – A, B and – C. Flinderole A was isolated from the stembark of the plant Flindersia acuminata with 0.001 % dry wt. yield. The other indole alkaloids, flinderoles –B and –C were isolated from the stembark of Flindersia amboinensis, collected from Papua New Guinea, yielding 0.016 and 0.014% dry wt., respectively.
Scientists are looking forward towards these indole alkaloids as promising drug candidate for malaria as these compounds have selective antimalarial activity. Flinderoles A-C showed inhibition of parasite growth with IC50 values between 0.15 and 1.42 µM against the Dd2 (chloroquine-resistant) Plasmodium falciparum strain with selectivity assessed using the HEK-293 mammalian cell line.
The novelty of the NCL work lies in the fact that the team achieved the total synthesis of two of the three flinderoles from 3-indole acetic acid, a commercially available raw material. Dr Dethe and his team achieved synthesis of flinderoles –B and –C with 17.2 % overall yield.
In this process, the NCL team developed a highly selective [3 +2] cycloaddition reaction between a tertiary alcohol and olefin for the synthesis of pyrroloindoles. The strategy can also be used for the synthesis of other natural products of the indole alkaloid category and their analogues.
Professor K.C. Nicolaou, Chairman, Department of Chemistry, The Scripps Research Institute and Professor of Chemistry at University of California, San Diego described this synthesis of flinderoles as breathtaking in its design and execution.These compounds are powerful antimalarial agents and thus represent promising leads for drug discovery and development in this area of research, he added.
He congratulated Dr. Dethe and his team for their brilliant work that could lead to new medicines in future.
NCL has filed a patent to protect intellectual property of the work.
- The author is head of Publication and Science Communication Unit, National Chemical Laboratory , Pune