61711-97-5Relevant academic research and scientific papers
Discovery of Potent, Reversible, and Competitive Cruzain Inhibitors with Trypanocidal Activity: A Structure-Based Drug Design Approach
De Souza, Mariana L.,De Oliveira Rezende Junior, Celso,Ferreira, Rafaela S.,Espinoza Chávez, Rocio Marisol,Ferreira, Leonardo L. G.,Slafer, Brian W.,Magalh?es, Luma G.,Krogh, Renata,Oliva, Glaucius,Cruz, Fabio Cardoso,Dias, Luiz Carlos,Andricopulo, Adriano D.
, p. 1028 - 1041 (2019/12/27)
A virtual screening conducted with nearly 4?000?000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
Regioselectivity of Photochemical and Thermal Smiles Rearrangements and Related Reactions of β-(Nitrophenoxy)ethylamines
Wubbels, Gene G.,Halverson, Ann M.,Oxman, Joe D.,Bruyn, Van H. De
, p. 4499 - 4504 (2007/10/02)
The ortho, meta, and para isomers of β-(nitrophenoxy)ethylamine (1, 2, and 3, respectively) have been synthesized as hydrochloride salts.The corresponding ortho, meta, and para isomer of β-(nitrophenoxy)ethyl alcohol (4, 5, or 6, respectively), the Smiles rearrangement product, is formed cleanly in alkaline water by a thermal reaction from 1 or 3 and by a photochemical reaction from the triplet state of 2.Photolysis of 1 or 3 does not cause Smiles rearrangement; photoproducts recovered from 1 and 3 show that β-amino group in both cases bonds at the ring carbon atom adjacent to the side chain and meta to the nitro group.The contrast of these results with those reported for photo-Smiles rearrangements of similar systems containing NHPh as the attacking nucleophile and for intermolecular aromatic photosubstitution by alkylamines is discussed.The results support the recently proposed "energy gap" model for predicting regioseelctivity in heterolytic nucleophilic aromatic photosubstitution.
