Viewpoint pubs.acs.org/jmc
In Vivo and In Vitro Optimization of Screening Antimalarial Hits toward Lead Molecules for Preclinical Development Tony Fröhlich and Svetlana B. Tsogoeva* Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Henkestrasse 42, 91054 Erlangen, Germany
ABSTRACT: In order to overcome one of the greatest challenges in malaria treatment, drug resistance, new drug candidates are urgently needed, which should preferably act via novel mechanisms. Successful optimization of a phenotypic screening hit based on a quinoline-4-carboxamide derivative resulted in the highly promising lead structure 4, which according to the Medicines for Malaria Venture (MMV) met the efficacy and drug metabolism and pharmacokinetics (DMPK) requirements for a malaria drug target candidate and consequently was selected for preclinical development.
T
maintaining antimalarial activity. Replacing the 3-pyridyl moiety with an ethyl linked pyrrolidine subunit (compound 3) improved aqueous solubility and metabolic stability. Last but not least, exchanging the tolyl group with a benzylmorpholine substituent gave the highly promising quinoline derivative 4 with greatly improved pharmacological properties compared to the chemical starting point 1: 100-fold higher antimalarial potency (EC50(P.f. 3D7) = 0.001 μM), better aqueous solubility (216 μM) as well as metabolic stability (mouse Cli < 0.9 mL min−1 g−1) and a lipophilicity that is comparable to orally administered drugs already available on the market (clogP < 3.5). Three different synthesis routes were applied in the course of this SAR study (Scheme 1), and in total, 30 different quinoline4-carboxamide derivatives were synthesized to accomplish the goal of hit-to-lead optimization. In general, it can be said that the preparation of each compound is straightforward, involves only 2−4 steps, and the yields are for the most part acceptable, especially for synthesis of the most promising drug candidate 4, although there is still room for improvement. In addition, all starting materials, such as 5-fluoroisatin, p-methylacetophenone, and 4-(bromomethyl)benzonitrile, are all commercially available and fairly inexpensive. The first synthesis route focused on the alteration of the halogen atom (R1) and the amide substituent (R2). Pfitzinger reaction between different isatin derivatives and p-methylacetophenone afforded the
o this day malaria still remains one of the most devastating diseases causing the death of 0.5 million people each year.1 The greatest challenge to be overcome in malaria treatment is upcoming drug resistance, which renders wellestablished drugs like chloroquine or artemisinin ineffective.2 In order to solve this problem, the development of new drug candidates is urgently needed. In this issue of Journal of Medicinal Chemistry Baragaña et al. report on their synthesis strategy and extensive SAR study of different quinoline-4carboxamide derivatives, which led to the discovery of compound 4 (Figure 1), a highly potent antimalarial agent, accomplished to reach preclinical development.3 The idea for the preparation of this compound originated from a phenotypic screen of the Dundee protein kinase library, which was performed against the blood stage of Plasmodium falciparum 3D7 strain.4 From over 4700 compounds several screening hits were identified, one of which was the 2,6-disubstituted quinoline-4-carboxamide scaffold 1 (Figure 1). The compound exhibited submicromolar activity against malaria parasites (EC50(P.f. 3D7) = 0.12 μM) and a good selectivity index with respect to a human cell line (MRC-5) (>100-fold) but at the same time was demonstrated to have suboptimal pharmaceutical properties: high lipophilicity (clogP > 4), poor metabolic stability (mouse liver microsomes Cli > 5 mL min−1 g−1), and limited aqueous solubility (
