257941-41-6Relevant academic research and scientific papers
Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei
Ferrins, Lori,Gazdik, Michelle,Rahmani, Rapha?l,Varghese, Swapna,Sykes, Melissa L.,Jones, Amy J.,Avery, Vicky M.,White, Karen L.,Ryan, Eileen,Charman, Susan A.,Kaiser, Marcel,Bergstr?m, Christel A. S.,Baell, Jonathan B.
, p. 6393 - 6402 (2014)
A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
Synthesis ofortho-arylated and alkenylated benzamides by palladium-catalyzed denitrogenative cross-coupling reactions of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids
Balakrishnan, Madasamy Hari,Kanagaraj, Madasamy,Mannathan, Subramaniyan,Ravva, Mahesh Kumar,Sankar, Velayudham
supporting information, p. 17190 - 17195 (2021/10/04)
An efficient palladium-catalyzed denitrogenative Suzuki-Miyaura type cross-coupling of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acid is described. The reaction is compatible with various aryl and alkenyl boronic acids affordingortho-arylated and alkenylated benzamides in good to high yields. Heteroaromatic boronic acids were also successfully employed. Along with this, a coupling reaction was established by using phenyl boronate ester as the coupling partner. The reaction is believed to proceedviaa five-membered aza-palladacyclic intermediate. DFT calculations were studied comparing the reactivity of palladium and nickel complexes in the five-membered aza-metallacycle formation from 1,2,3-benzotriazin-4(3H)-ones. The application of the reaction was successfully demonstrated by convertingortho-alkenylated products toortho-alkylated products in high yieldsviaa reduction reaction.
3D-QSAR and 3D-QSSR models of negative allosteric modulators facilitate the design of a novel selective antagonist of human α4β2 neuronal nicotinic acetylcholine receptors
Henderson, Brandon J.,Orac, Crina M.,MacIagiewicz, Iwona,Bergmeier, Stephen C.,McKay, Dennis B.
scheme or table, p. 1797 - 1813 (2012/04/10)
Subtype selective molecules for α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have been sought as novel therapeutics for nicotine cessation. α4β2 nAChRs have been shown to be involved in mediating the addictive properties of nicotine while other subtypes (i.e., α3β4 and a7) are believed to mediate the undesired effects of potential CNS drugs. To obtain selective molecules, it is important to understand the physiochemical features of ligands that affect selectivity and potency on nAChR subtypes. Here we present novel QSAR/QSSR models for negative allosteric modulators of human α4β2 nAChRs and human α3β4 nAChRs. These models support previous homology model and site-directed mutagenesis studies that suggest a novel mechanism of antagonism. Additionally, information from the models presented in this work was used to synthesize novel molecules; which subsequently led to the discovery of a new selective antagonist of human α4β2 nAChRs.
