N-(4-ethylbenzoyl)-2-hydroxybenzamide (1 ) was identified in a high-throughput screening of a small molecule collection satisfying the Lipinski's rule of five. Compound 1  was active in vitro against Toxoplasma gondii parasites in nanomolar range (IC50 = 32 nM) with no apparent toxicity against human foreskin fibroblasts (HFF) at the highest (10 uM) compound's concentration.1 The hit compound 1  was selected for further rounds of structure optimization in search of derivatives with improved potency and ADME/Tox properties.In general, a wide range of N-benzoyl-2-hydroxybenzamides and related compounds was synthesized and evaluated for efficacy against five protozoan parasites: Toxoplasma gondii, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum.1,2Structure-activity analyses led to the identification of compounds with excellent activity, and in some cases selectivity, against T. gondii, the K1 isolate of P. falciparum and L. donovani.  On the other hand, these analogs were only moderately active against T. cruzi. The lead compound 2  exhibited an IC50 of 0.005 �g/mL against the K1 P. falciparum isolate, and showed excellent selectivity index, SI = 1640. The compound's potency against the K1 isolate was 21-fold superior to that of the standard anti-malarial drug, chloroquine (IC50 0.108 �g/mL). The activity of another compound in this series (3 , IC50 0.135 �g/mL) against L. donovani was comparable to that of miltefosine (IC50 0.188 �g/mL), an orally administered drug currently in use to treat leishmanial infections.2This research study characterizes N-benzoyl-2-hydroxybenzamides as highly effective anti-protozoal agents with the potential for further development.  Figure 1.  Structural optimization of hit 1  afforded highly active lead compounds 2  and 3   References(1)   Stec, J.; Huang, Q.; Pieroni, M.; Kaiser, M.; Fomovska, A.; Mui, E.; Witola, W.; Bettis, S.; McLeod, R.; Brun, R.; Kozikowski A.P. Synthesis, Biological Evaluation and Structure-Activity Relationships of N-Benzoyl-2-hydroxybenzamides as Agents Active against P. falciparum (K1 strain), Trypanosomes, and Leishmania.J. Med. Chem. 2012 , 55, 3088�3100.(2)   Fomovska, A.; Huang, Q.; Bissati, K.E.; Mui, E.; Witola, W.H.; Cheng, G.; Zhou, Y.; Sommerville, C.; Roberts, C.W.; Bettis, S.; Prigge, S.T.; Afanador, G.A.; Hickman, M.R.; Lee, P.J.; Leed, S.E.; Auschwitz, J.M.; Pieroni, M.; Stec, J.;Muench, S.; Rice, D.; Kozikowski, A.P.; McLeod R. Unique Parasite Secretory Pathway Disrupted by Novel Hydroxybenzamides. Antimicrob. Agents Chemother. 2012, 2666 �2682.

<i>N</i>-Benzoyl-2-hydroxybenzamides displayed high activity against protozoan parasites

248th National Meeting (2014)

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N-Benzoyl-2-hydroxybenzamides displayed high activity against protozoan parasites