Expanding the Antimalarial Drug Arsenal—Now, But How.docVIP

Pharmaceuticals 2011, 4, 681-712; doi:10.3390/ph4050681 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Expanding the Antimalarial Drug Arsenal—Now, But How? Brian T. Grimberg * and Rajeev K. Mehlotra * Center for Global Health and Diseases, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; E-Mails: brian.grimberg@ (B.T.G.); rajeev.mehlotra@ (R.K.M.); Tel.: +1-216-368-6328 or +1-216-368-6172, Fax: +1-216-368-4825. Received: 16 January 2011; in revised form: 9 April 2011 / Accepted: 19 April 2011 / Published: 26 April 2011 Abstract: The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i) re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii) repurposing drugs that are currently used to treat other infections or diseases; (iii) chemically modifying existing antimalarial compounds; (iv) exploring natural sources; (v) large-scale screening of diverse chemical libraries; and (vi) through parasite genome-based (“targeted”) discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we