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. 2022 Sep;102(3):172–182. doi: 10.1124/molpharm.122.000549

Fig. 2.

Fig. 2.

Optimized pyridazinones inhibit PSAC and P. falciparum growth. (A) Screening hit MBX-2366, zones used to guide synthetic strategy, and key findings. (B) Structures and properties of MBX-2366 and optimized derivative MBX-4055. (C) Mean ± S.D. residual PSAC-mediated permeabilities (P) at indicated concentrations of MBX-2366, MBX-3318, and MBX-4055 (black, turquoise, and red symbols, respectively; n = 3–5 independent dose response trials for each inhibitor). Lines indicated best fits to the Langmuir isotherm: P = a/(1 + (x/K0.5)). (D) Normalized in vitro parasite growth with indicated inhibitor concentrations in PGIM and RPMI (red and black symbols, respectively). Symbols reflect mean ± S.D. of triplicate wells in a dose response experiment and are representative of 2–5 trials for each compound. Improved killing in PGIM indicates action on nutrient acquisition and establishes primary action on nutrient acquisition. (E) Correlation between PSAC block and in vitro growth inhibition for 79 pyridazinone derivatives. Black, turquoise, and red symbols represent MBX-2366, MBX-3318, and MBX-4055, respectively. Pearson correlation coefficient for K0.5 and IC50 values, r = 0.81; p < 10−4.