Imidazoline- and Benzamidine-Based Trypanosome Alternative Oxidase Inhibitors: Synthesis and Structure–Activity Relationship Studies

Abstract

The trypanosome alternative oxidase (TAO), a mitochondrial enzyme involved in the respiration of the bloodstream form trypomastigotes of Trypanosoma brucei , is a validated drug target against African trypanosomes. Earlier series of TAO inhibitors having a 2,4-dihydroxy-6-methylbenzoic acid scaffold (“head”) and a triphenylphosphonium or quinolin-1-ium cation as a mitochondrion-targeting group (“tail”) were shown to be nanomolar inhibitors in enzymatic and cellular assays. We investigated here the effect of different mitochondrion-targeting cations and other scaffold modifications on the in vitro activity of this class of inhibitors. Low micromolar range activities were obtained, and the structure–activity relationship studies showed that modulation of the tail region with polar substituents is generally detrimental to the enzymatic and cellular activity of TAO inhibitors.

Alternative Oxidase: From Molecule and Function to Future Inhibitors

“…Among them the most active compound for inhibiting TAO 6K, EC 50 = 2.7 μM) had outstanding inhibitory effect on T. brucei. 168 In addition to chemical synthesis, natural products are also important sources of AOX inhibitors. The anti-trypanosomal properties of…”

“…To further improve the activities of compounds with the 2,4-dihydroxy-6-methylbenzoic acid scaffold, the structure–activity relationship of imidazoline- and benzamidine-based TAO inhibitors was measured (Figure H–K). Compounds including 2-phenylimidazolin-3-ium (Figure I, EC 50 = 1.72 μM), benzamidinium ( n = 12 in Figure J, EC 50 = 3.3 μM), and 2-(phenylamino)­imidazolin-3-ium (R = H in Figure K, EC 50 = 2.7 μM) had outstanding inhibitory effect on T. brucei . In addition to chemical synthesis, natural products are also important sources of AOX inhibitors.…”

“…Compounds including 2-phenylimidazolin-3-ium ( Figure 6 I, EC 50 = 1.72 μM), benzamidinium ( n = 12 in Figure 6 J, EC 50 = 3.3 μM), and 2-(phenylamino)imidazolin-3-ium (R = H in Figure 6 K, EC 50 = 2.7 μM) had outstanding inhibitory effect on T. brucei . 168 In addition to chemical synthesis, natural products are also important sources of AOX inhibitors. The anti-trypanosomal properties of Anogeissus leiocarpa extracts and their inhibitory effect on TAO have been identified.…”

Medicinal Chemistry in Portugal and Spain: A Strong Iberian Alliance

“…leaves as modulators of Pglycoprotein activity (Milica Pesǐc, Patrı ́cia Rijo, et al), 14 and imidazoline-and benzamidine-based trypanosome alternative oxidase inhibitors (Christophe Dardonville et al). 15 Viewpoints provide overviews on computational prediction of pK a values in small molecules and proteins (Gonzalo Jimeńez-Oseś et al) 16 and antivirals against (re)emerging flaviviruses (Marı ́a-Jesuś Peŕez-Peŕez et al…”

“…Letters cover subjects such as discovery of novel tripeptides as integrin-linked kinase modulating agents (Javier Garcia-Marin, Juan J. Vaquero, Diego Rodrı́guez-Puyol, et al), peptide shuttles for brain delivery (Miquel Vila-Perelló, Vera Neves, et al), triazene hybrids for the treatment of melanoma (Maria Jesus Perry et al), SAR of oxindole–lactam hybrids as selective butyrylcholinesterase inhibitors (Marta Pineiro et al), 2-prenylated alkoxylated benzopyrans with PPARα/γ agonist activity (Nuria Cabedo, Diego Cortes, et al), triple PI3K/mTOR/PIM inhibitors (Joaquı́n Pastor et al), piperazinyl bicyclic derivatives as selective calcium channels ligands (Carmen Almansa et al), indole-containing pyrazino­[2,1- b ]­quinazoline-3,6-diones active against Plasmodium and trypanosomatids (Fátima Nogueira, Emı́lia Sousa, et al), evaluation of non-orthosteric interactions with potent and selective A 3 antagonists (José Brea, Hugo Gutiérrez-de-Terán, Eddy Sotelo, et al), steroid–quinoline hybrids to prevent protein aggregation (Artur M. S. Silva et al), the BASHY platform for the assembly of a fluorescent bortezomib–GV1001 conjugate (Uwe Pischel, Sandra N. Pinto, Pedro M. P. Gois, et al), pyridazin-3­(2 H )-one guanidine-based derivatives as DNA binders (Carmen Terán et al), compounds from Plectranthus mutabilis Codd. leaves as modulators of P-glycoprotein activity (Milica Pešić, Patrı́cia Rijo, et al), and imidazoline- and benzamidine-based trypanosome alternative oxidase inhibitors (Christophe Dardonville et al) . Viewpoints provide overviews on computational prediction of p K a values in small molecules and proteins (Gonzalo Jiménez-Osés et al) and antivirals against (re)­emerging flaviviruses (Marı́a-Jesús Pérez-Pérez et al) …”