Figure 3.

Structure–activity relationships (SAR) of DHPM-thione series. (A) Heat map representation of the dose–response curves for 82 DHPM-thiones. Compounds are sorted from highest efficacy to lowest efficacy. Red indicates rescue (OD600 values), white indicates no rescue. Doses of compounds increased from left to right and range from 2 to 40 μM. The inactive cluster of R¹-unsubstituted DHPM-thiones is indicated at the bottom of the heat map. (B) General structures of isobutyl and substituted/unsubstituted benzyl DHPM-thione analogues indicated in yellow and green, respectively, in the following plots. The left plot is efficacy and right plot is potency of all analogues falling within that substitution pattern. The y-axis for efficacy is fraction of maximal rescue by the series and the y-axis for potency is EC₅₀ (μM). The indicated P-values were calculated according using a Student’s t test. (C) Structures of the thiourea analogue, 10{3,3,1}, and the urea variant, 11. (D) Dose–response curves of 10{3,3,1}, 11, CQ, and monastrol. X-axis is concentration (μM) on a log₂ scale, and y-axis is % of the maximal CQ response. (E) Summary of SAR for R¹, R², R³, and S/O urea. While significant tolerability existed within the R¹ and R² groups, a benzylic substitution at the R¹ group was preferred. The thiourea was required, as was at least an alkyl group at R¹. Both ketone and ester groups were well-tolerated at R³.