Discovery of new antimalarial chemotypes through chemical methodology and library development

Abstract

In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC(50)'s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.

Fig. 1.

Principle moments of inertia analysis of the CMLD-BU compound collection.

Fig. 2.

Active series from the CMLD-BU compound collection vs. ability to inhibit the viability of five geographic P. falciparum lines. Scaffolds of active series, polycyclic ketal (1), indoline alkaloid (2), and dihydropyrimidinone (3), and activity of representative compound as identified in qHTS (A–C) and follow-up confirmation (D–F). Plots show the compound potency against five geographic P. falciparum lines (square, 7G8; up triangle, Dd2; down triangle GB4; diamond, HB3; CP250 open circle) as determined in the SYBR Green-based viability assay in qHTS (A–C) and in a 12-point follow-up titration (D–F).

Fig. 3.

General cycloisomerization/annulation route to polycyclic ketals and polycyclic ketal library building blocks.

Fig. 4.

General route to indoline alkaloid scaffolds.

Fig. 5.

(A) Organocatalytic asymmetric synthesis of dihydropyrimidinone scaffolds. (B) Synthesis of DHP-derived guanidine library. Reagents: (i) 2 equivalent Lawesson’s reagent, PhCh₃, reflux, 48 h. (ii) 20 equivalent CH₃I, CH₃CN, 75 °C, 2 h. (iii) R⁵-NH₂, CH₃CN, 83 °C, 36 h.

Fig. 6.

Heat map analysis of DHP compounds. (A) Results were ranged in order of effective concentrations necessary to inhibit proliferation at 50% (IC₅₀) in the GB4 line. The resulting structures were then clustered and fold selectivity calculated for IC₅₀. (B) Magnification of most active compounds. (C) Substructure analysis of the most active compounds. (D) Compounds 3a and 3b exhibiting the highest level of 7G8 IC₅₀/GB4 IC₅₀ selectivity.