Selective Inhibitors of Monoamine Oxidase. 4. SAR of Tricyclic N-Methylcarboxamides and Congeners Binding at the Tricyclics' Hydrophilic Binding Site

Abstract

Linear [6.6.6] tricyclic moieties whose center ring is made of two atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings, including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sulfone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the "cheese effect" (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing tyramine).

Synthesis of Active Hexafluoroisopropyl Benzoates through a Hydrogen‐Bond‐Enabled Palladium(II)‐Catalyzed C−H Alkoxycarbonylation Reaction

“…Thus, the directing group was efficiently installed onto 9 by sequential iodination ( 10 ) and silylation ( 1 z ) reactions –. Next, an efficient and selective C−H alkoxycarbonylaton reaction produced the corresponding ester, which upon subsequent amidation and desilylation delivered the benzocoumarin amide 11 , a potential monoamine oxidase inhibitor …”

“…[21] Accordingly,t his approach represents an unprecedented protocol for meta C À Halkoxycarbonylation of tetrahydroquinoline.Moreover,the 3,4-benzocoumarin core 9,awidely found motif in natural and bioactive molecules, [22] was also functionalized using this methodology (Scheme 2B). [23] As peculative mechanism for this alkoxycarbonylation reaction is depicted in Scheme 3. See the Supporting Information for experimental details.…”

Synthesis of Active Hexafluoroisopropyl Benzoates through a Hydrogen‐Bond‐Enabled Palladium(II)‐Catalyzed C−H Alkoxycarbonylation Reaction

“…[7a-d] Next, an efficient and selective C À Ha lkoxycarbonylaton reaction produced the corresponding ester, which upon subsequent amidation and desilylation delivered the benzocoumarin amide 11,apotential monoamine oxidase inhibitor. [23] As peculative mechanism for this alkoxycarbonylation reaction is depicted in Scheme 3. First, 1,u pon exposure to the Pd II complex A and HFIP alcohol produces the complex B,w hich undergoes C À Hp alladation [24] to generate the complex C.Asubsequent migratory insertion of CO into the Pd À Cb ond and the ligand exchange produce as evenmembered palladacycle D,which upon reductive elimination delivers product 2 and releases aP d 0 species,w hich requires an oxidation to re-enter the catalytic cycle.…”

Predicting Monoamine Oxidase Inhibitory Activity Through Ligand-Based Models

“…8). The dataset of 65 compounds previously published [121,147,148] was divided in training set (52 compounds were used to generate the pharmacophoric model) and test set (13 compounds). Pharmacophore modeling was developed with the help of Maestro software [149] through Phase module [150] that combines conformational sampling with different scoring methods to identify pharmacophoric hypothesis.…”