Toward More Drug Like Inhibitors of Trypanosome Alternative Oxidase

Abstract

New tools are required to ensure the adequate control of the neglected tropical disease human African trypanosomiasis. Annual reports of infection have recently fallen to fewer than 5000 cases per year; however, current therapies are hard to administer and have safety concerns and, hence, are far from ideal. Trypanosome alternative oxidase is an exciting target for controlling the infection; it is unique to the parasite, and inhibition of this enzyme with the natural product ascofuranone has shown to clear in vivo infections. We report the synthesis and associated structure activity relationships of inhibitors based upon this natural product with correlation to T. b. brucei growth inhibition in an attempt to generate molecules that possess improved physicochemical properties and potential for use as new treatments for human African trypanosomiasis.

Alternative oxidase inhibitors: Mitochondrion‐targeting as a strategy for new drugs against pathogenic parasites and fungi

“…Structure‐activity relationship of colletochlorin B. IC 50 values for the inhibition of purified recombinant trypanosome alternative oxidase reported by West et al and Saimoto et al (left and right IC 50 values, respectively)…”

“…After the groups of Kita, investigating the pharmacophore of AF ( 188 ), reported that the electron withdrawing cyano group was a useful alternative to its formyl group, West et al investigated the SAR of 3‐chloro‐4‐hydroxybenzonitrile analogues. With the aim of reducing the lipophilicity of the tail region of inhibitor 200 , and thereby improve its physicochemical properties including the predicted CNS multiparameter optimization score, they introduced different polar groups (amide and ether) in the lipophilic tail (Figure ) . A large decrease in inhibition potency compared with the n ‐octyl analogue ( 190 ) was observed with amide ( 191‐196 ) and ether groups ( 197‐199 ), showing that even minor increases in polarity in this part of the lipophilic tail are not tolerated.…”

“…A large decrease in inhibition potency compared with the n ‐octyl analogue ( 190 ) was observed with amide ( 191‐196 ) and ether groups ( 197‐199 ), showing that even minor increases in polarity in this part of the lipophilic tail are not tolerated. The introduction of polarity at the terminal part of the chain ( 195 , 196 , 198 , and 199 ) seemed to be somewhat better tolerated but these compounds were inactive in vitro against T. brucei brucei , probably because of poor cellular uptake. This shows that alternative strategies are needed to improve the physicochemical properties of these TAO inhibitors.…”

“…3‐Chloro‐4‐hydroxybenzonitrile derivatives: influence of tail hydrophilicity and methylene chain length on recombinant trypanosome alternative oxidase inhibition…”

“…As discussed above, known inhibitors of TAO (SHAM and AF) had earlier been discovered, making SADD targeting of TAO much easier. Guided by the TAO structure, efforts are currently ongoing to modify AF and SHAM structures to obtain more potent inhibitors with better drug‐like properties …”