Evaluation of Diarylureas for Activity Against Plasmodium falciparum

Abstract

A library of diarylurea IGFR inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…MMV006901 ( 597 ) is currently unreported for antimalarial activity; however, Kiplin and co‐workers identified a series of diaryl ureas (e.g., 598 ) as a promising new class of antimalarials . MMV688283 ( 33 ), discussed above, featured in the kinetoplastid category of the Pathogen Box, but was reported as an antimalarial, albeit with similar compounds being reported as kinetoplastid inhibitors .…”

Novel diaryl ureas with efficacy in a mouse model of malaria

“…The pharmacophore differs from that constructed by Zhang et al which contained 2-3 hydrophobic features and 2-3 hydrogen bond acceptors. 25 Not surprisingly, the 3 most active diaryl ureas from the paper by Zhang et al failed to map to our pharmacophore; most likely, the 4-aminoquinaldine-derived diaryl ureas present different features than the triclosan-derived diaryl ureas. Distinctions in the arrangement of hydrophobic and hydrogen bonding features in the diaryl ureas from Zhang et al and in this study may enable these molecules to target different proteins in Plasmodium falciparum.…”

“…4 We also reported in 2005 the preparation of triclosan-based 4'-ureas (Supplementary Data Figure S1) that were less potent against cultured parasite (EC 50 values of ~100 μM) than 12 -25, but exhibited IC 50 values of ~100 nM against purified PfFabI assayed in vitro. 14 More generally, the diaryl urea class of small molecules has been previously reported in the literature to exhibit potent efficacy against cultured parasites [21][22][23][24][25] but without definitive biological target identification. This chemotype was also found amongst hits against P. falciparum dihydroorotate dehydrogenase 26 that lacked whole-cell activity.…”

Phosgene-free synthesis of N-aryl-N'-4-pyridinylureas via selenium-catalyzed oxidative carbonylation of 4-aminopyridine with aromatic amines

“…9 In recent years, great efforts have been paid to the development of phosgenefree approaches to these compounds. For example, triphosgene, 9-11 chloroformate, 12,13 and N,N'-carbonyldiimidazole (CDI) 14 have been developed as the substitutes for phosgene. However, low atom economy limits the utility of these approaches.…”