Antitrypanosomal Lead Discovery: Identification of a Ligand-Efficient Inhibitor of Trypanosoma cruzi CYP51 and Parasite Growth

Abstract

Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi, and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…We hypothesized that higher doses of posaconazole could lead to greater inhibition of parasite CYP51 and improved rates of cure of infected mice. If so, this result would provide an encouraging rationale for the development of improved CYP51 inhibitors that are currently being optimized for Chagas disease treatment (7,(20)(21)(22)(23)(24)(25)(26). As observed earlier, all posaconazole regimens suppressed T. cruzi parasitemia below the detection limit at the end of treatment.…”

“…with various regimens of benznidazole (10,30, and 100 mg/kg q.d.) and posaconazole (10,20,30, and 100 mg/kg q.d.). In experiments that included regimens of various durations, the longest treatment regimen was initiated on day 35 postinfection.…”

Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs

“…In the ligand-free and sterol-bound structures, it forms the hydrogen bond with the heme ring A propionate, but binding of strong inhibitors often disrupts this hydrogen bond (29,39,49). The hydrogen bond between Tyr 136 (phenylalanine in plant CYP51, tyrosine in all other phyla) was also found disrupted in several CYP51-inhibitor complexes (29,40,53).…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…1PKL [254]; 3E0V, 3E0W [255]; 3IS4, 3KTX [256]; 3HQN, 3HQO, 3HQP, 3HQQ [257]; 3PP7, 3QV6, 3QV7, 3QV8, 3QV9 [258]; 3SRK [259] 3KHD [260] 4HYV, 4HYW [261]; 4KCT, 4KCU, 4KCV, 4KCW [262] 3PP7, 3QV6, 3QV7, 3QV8, 3QV9 [258] Ribulose 5-phosphate 3-epimerase (a1RPE) 1TQX [265] RNA Editing ligase 1 (REL1) 1XDN [266] S-Adenosylhomocysteine hydrolase (SAHH) 3G1U [267] 1V8B [268] 3H9U [269] Seryl-tRNA synthetase (SerRS) 3LSQ, 3LSS [270] Sirtuin 2A (Sir2A) 3U31, 3U3D [271] Spermidine synthase (SpdSyn) 2HTE [136] ; 2I7C, 2PSS, 2PT6, 2PT9 [272]; 3B7P; 2PWP [273]; 3RIE [274] 3BWC [275] Sterol 14-α Demethylase (CYP51) 3L4D [276] 3G1Q, 3GW9 [277]; 2WV2, 2X2N [278]; 3P99 [279]; 3TIK [280]; 4BJK [281]; 4G7G, 4G3J [282]; 2WUZ, 2WX2 [278]; 3K1O, 3KHM, 3KSW [283]; 4H6O [284]; 3ZG2, 3ZG3 [285]; 4COH [286]; 4BY0 [287] ; 4BMM [288] Sterol carrier protein, type 2 thiolase (SCP2-thiolase) 3ZBG, 4B19 [289] 4BI9 [289] Superoxide dismutase (SOD) 2BPI [290] 3ESF [291] 2GPC [291] Terminal RNA uridyltransferase (TUTase)…”