Background: Two pyridine derivatives were identified as promising drug candidates in animal models of Chagas disease. Results: They were tested as sterol 14␣-demethylase (CYP51) inhibitors, and x-ray co-structures with T. cruzi CYP51 were determined.
Conclusion:The structures explain the potency and selectivity of the compound. Significance: Structural information contributes to a better understanding of P450 inhibition and will facilitate rational design of pathogen-specific drugs.
A structure–activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo-[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).
We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
Chagas
disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health.
Available medicines were introduced over 40 years ago, have undesirable
side effects, and give equivocal results of cure in the chronic stage
of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed
curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic,
show no adverse effects in vivo following repeat dosing, are prepared
by a short synthetic route, and have druglike properties suitable
for preclinical development.
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