Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration.

摘要: American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains serious global health problem. The current available treatment for CD limited to two nitroderivatives with efficacy and several side effects. rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents promising strategy fungi trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In present work, we evaluate through different approaches (molecular docking, structure relationships, inhibitory assay, phenotypic screenings vitro vivo) potency selectivity novel inhibitor (compound 1) its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active EC50 3.86 4.00 μM upon intracellular (Tulahuen strain) bloodstream forms (Y strain), respectively. vivo assays showed that reduced 43% parasitemia peak but, unfortunately failed promote animal survival. order an enhancement at pharmacological properties, 17 new were purchased screened vitro. Our findings demonstrated five compounds forms, highlighting 1e 1f, 2.20 2.70 μM, respectively, indices (SI) = 50 36, Against trypomastigotes, 1f reached value 20.62 μM, similar range Benznidazole, but low SI (3). Although improved solubility 1, analogue did not enhance neither better mouse model acute infection arguing synthesis pyrazolo[3,4-e][1,4]thiazepin derivatives aiming contribute alternative therapies CD.