Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents

Abstract

A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 of 0.65 µM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14–18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 µM). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis.

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.…”

Primary targets of the sesquiterpene lactone deoxymikanolide on Trypanosoma cruzi

“…Since parasites lack a heme biosynthetic pathway and based on the importance of this cofactor for parasite survival and growth (Choi et al, 2013), we evaluated if this could be a molecular target for deoxymikanolide. In view of the results presented herein, the compound has no affinity for hemin, so hemin would not be a target for this compound.…”

Drug Strategies Targeting CYP51 in Neglected Tropical Diseases

“…Most of these derivatives displayed strong inhibitory potency to T. cruzi with single digit nanomolar EC 50 or less. 154 In addition, 70 and 72 showed significantly improved in vitro microsomal stability (compared to 66 and 67 ) by replacing the cyclohexyl unit with an aromatic ring of which potential susceptible sites are blocked with halogen atoms and/or an additional aromatic ring. Furthermore, 72 showed significantly decreased inhibition against human CYP1A2, CYP2C9, CYP2D6, and CYP3A4 enzymes with −26%, 41%, −17%, and 15% percent inhibition at 1 μM, respectively.…”

“… 143 On the basis of potency in cell-based assays and in a mouse model of T. cruzi infection, 143 , 145 the N -indolyl-oxopyridinyl-4-aminopropanyl analogue, LP10 ( 16 , Figure 12 ), was selected as a starting point for hit-to-lead optimization. Rounds of analogue design, compound synthesis, testing, and analysis of structure–activity and structure–property relationships led to substantially improved inhibitors, 147 , 151 , 152 , 154 as discussed in section 5.2 .…”