Synthesis, Stereochemical Identification, and Selective Inhibitory Activity against Human Monoamine Oxidase-B of 2-Methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones

Abstract

A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC50 values ranging between 26.81 +/- 2.74 microM and 14.20 +/- 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.

Investigations on the 2-thiazolylhydrazyne scaffold: Synthesis and molecular modeling of selective human monoamine oxidase inhibitors

“…The presence and the position of a methyl group linked to the pyridine ring deeply affect the hMAO inhibitory activity (18, 20, and 22) showing the lowest IC 50 when it was introduced in the meta-position. From the results obtained in this and in our previous works, [8][9][10] it is possible to state that moieties on the C4 of the thiazole ring must be carefully evaluated. Molecular modeling studies proved that this region was involved in the interaction between inhibitor and FAD cofactor which was placed inside the active site of the enzyme and was responsible of its oxidative activity.…”

“…Furthermore, numerous substituted hydrazines have been studied as MAO inhibitors and their specific mechanism of action was fully investigated. 7 Substituents on the aromatic ring at C4 position of thiazole ring also influenced the activity as demonstrated by the introduction of several groups (NO 2 , CN, CH 3 , and OCH 3 ) or halogens (F and Cl) in the ortho and para positions in our previous works, 8,9 while the introduction of more steric hindered coumarin and naphthalene nucleus at C4 position of thiazole led to a decreased hMAO inhibitory activity. 10 That prompted us to evaluate the presence of an electron-donating group such -OCH 3 in the meta-position of the aryl ring.…”

Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies

“…The interactions of the synthesized fluorinated methoxylated chalcones with hMAO isoforms were determined by a fluorimetric method described and modified previously [19][20][21]. Study medium contained 0.1 mL of sodium phosphate buffer (0.05 M, pH 7.4), various concentrations of the newly synthesized compounds or reference compounds, and adequate amounts of recombinant hMAO-A or hMAO-B.…”

Exploring the thiazole scaffold for the identification of new agents for the treatment of fluconazole resistant Candida

“…Moreover, very similar compounds were reported as potent and selective monoamine oxidase inhibitors 25,26 .…”