Resumen de Chapter Two - Medicinal chemistry progression of antimalarial hits from phenotypic whole cell screening of SoftFocus libraries
Peter M. Cheuka, Godfrey Mayoka, John Okombo, Kelly Chibale
Malaria continues to be endemic in tropical and subtropical regions of Africa, Central and South America, Asia and Oceania. In 2016, over 400,000 deaths and approximately 220 million cases were recorded according to the World Health Organization. Once effective and cheap drugs such as chloroquine and sulfadoxine-pyrimethamine have been rendered ineffective by widespread resistance. Sadly, in South-East Asia, there is growing evidence of emerging resistance to the current first-line treatments, the artemisinin-combination therapies. Therefore, there is a critical need to develop new and affordable antimalarials which are not prone to resistance mechanisms that have rendered current therapies ineffective. In this chapter, the epidemiology, pathophysiology and current malaria treatments including associated challenges are reviewed. Common approaches to antimalarial drug discovery such as target- and phenotypic whole-cell-based approaches with their merits and demerits are also discussed. We further discuss Plasmodium falciparum kinases as a promising family of enzymes that could be exploited in antimalarial drug discovery. We then review case studies involving phenotypic hit identification, hit-to-lead and lead optimization and mechanism of action studies of four antimalarial chemotypes derived from phenotypic whole cell screening of SoftFocus libraries—aminopyridines, aminopyrazines, imidazopyridines and imidazopyridazines. Although hurdles encountered during lead optimization phases (such as poor solubility, a hERG inhibition liability, lack of acceptable in vivo efficacy and atypical dose-response curves) have precluded the progression of the latter two chemotypes, studies on the aminopyridines and aminopyrazines have delivered clinical (MMV390048) and preclinical (UCT943) candidates, respectively.
