Fig. 5: A SAR analysis reveals potent NPD8790 analogs with similar bioactivity.
From: Identification of a family of species-selective complex I inhibitors as potential anthelmintics
a Screening results of 1,280 benzimidazole-containing compounds (50 µM) against L1 wild-type C. elegans in the KCN survival assay (see Methods). Survival and overall health of worms was assessed relative to DMSO controls by monitoring worm motility 3 h after the removal of KCN. Data were sorted by relative motility score and hits were identified as compounds that reduced motility below 0.25; 84 hits were identified. b Log IC50 values of 51 NPD8790 analogs against the in vitro activity of complex I from wild-type C. elegans (N2) mitochondria; compounds are arranged in ascending order of potency (IC50); the position of NPD8790 is highlighted in red. c Fold-change in IC50 between the in vitro activity of B. taurus and C. elegans complex I for 43 NPD8790 analogs; compounds are arranged in ascending order of C. elegans selectivity; NPD8790 and related scaffolds are highlighted in red and orange, respectively. d and e Comparison of the inhibitory potency (IC50 values) of NPD8790 analogs against C. elegans complex I when subdivided on chemical structure: (d) the benzimidazole core position from which tail moieties originate (i.e., 1’ or 2’) or (e) the number of linker atoms in the tail moiety (i.e., 1, 2, 3, 4, 5). The position of NPD8790 is highlighted in white; analogs with either 5’ sidechain substitutions (n = 0) or sidechain lengths of 0 (n = 1) or 10 (n = 1) were insufficient for comparison. Within each boxplot, black horizontal lines denote group medians, boxes span from the 25th to the 75th percentile of each group’s distribution, and whiskers extend to the maximum and minimum values. f Chemical structures of class A, B and C benzimidazole analogs. g Dose-response curves for NPD8790 (Class A) and two analogs (5567167, Class B; 7925804, Class C) against the in vitro activity of complex I from wild-type C. elegans (N2) mitochondria. IC50 values estimated from fitted curves and fold-changes in potency among NPD8790, 5567167 and 7925804 are highlighted on the plot. Data are the mean of at least three biological replicates; error bars represent SEM.
