Selective and Potent Monoamine Oxidase Type B Inhibitors: 2-Substituted 5-Aryltetrazoles Derivatives

Abstract

Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectively rat brain monoamine oxidase (MAO) B over MAO A. Most of them were MAO B inhibitors and those bearing a substituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 microM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37,000 for 16a. The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests. The 5-[4-(phenylmethoxy)phenyl]-2-(2-cyanoethyl)tetrazole (16a) its derivative 16h and the 5-[4-(phenylmethoxy)phenyl]-2-(2-hydroxyethyl)tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors. Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now. This compound was selected for ex vivo experiments and was shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg. The structure-activity approach gives rise to the great importance of lipophilicity over electronic effects of the compounds in these series.

Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the α-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide

“…Using the mixed anhydride coupling (MAC) method, 18 we coupled ( R )- N - tert -butoxycarbonyl- d -serine (( R )- 24 ) with the substituted (4-(benzyloxy)phenyl)methanamines 20 – 23 to give amides ( R )- 25 –( R )- 28 , respectively, without racemization of the C(2) chiral center. The substituted ((benzyloxy)phenyl)methanamines were prepared by treating 4-cyanophenol ( 11 ) with the substituted benzyl bromides 12 – 15 and K 2 CO 3 in acetone to provide nitriles 16 – 19 , 19 , 20 respectively, which were then reduced (LiAlH 4 ) to give amines 20 – 23 . Methylation (CH 3 I, Ag 2 O) of the serine hydroxyl group in ( R )- 25 –( R )- 28 yielded ethers ( R )- 29 –( R )- 32 , respectively.…”

A direct continuous fluorometric turn-on assay for monoamine oxidase B and its inhibitor-screening based on the abnormal fluorescent behavior of silole

“…The IC 50 value was determined from plot of inhibition percentage, calculated in relation to a sample of the enzyme treated under the same conditions without inhibitor, versus Àlog C inhibitor . 40,41 The 'inhibition percentage' was estimated as follows: 'inhibition percentage' ¼ F (inhibitor) À F (no inhibitor) /F 0 À F (no inhibitor) , in which the F (no inhibitor) and F (inhibitor) refer to the fluorescence intensity at 467 nm of solution containing silole 1 (7.5 Â 10 À5 M), heptylamine (2.0 Â 10 À4 M), NaHSO 3 (1.0 Â 10 À4 M) and MAO-B (2.2 mg/mL) in the absence and presence of pargyline$HCl (0, 15, 30, 60, 120 mM), respectively; F 0 refers to the fluorescence intensity of the ensemble at 467 nm in the absence of MAO-B and inhibitor.…”

Design, synthesis and antibacterial activity of novel ketolides bearing an aryltetrazolyl-substituted alkyl side chain

“…Starting from aromatic nitriles or aromatic aldehydes, the 5-aryl tetrazoles were prepared by (2+3) cycloaddition of nitriles and azides according to the literature procedure. 40,[42][43][44] A process similar to Gabriel reaction was applied to achieve 5-aryl-tetrazolyl alkylamines. The N-alkylation on tetrazoles 3 were carried out with N-(3-bromopropyl) phthalimide, N-(4-bromobutyl) phthalimide or N-(5-bromopently) phthalimide to get 4, which were then hydrazinolyzed to produce amines 5.…”

“…38 The tetrazole is frequently employed in the lead optimization of ethical drug candidates. The tetrazole-containing compounds were found in various drugs such as matrixmetalloproteinase (MMP) inhibitors, 39 monoamine oxidase B inhibitors, 40 antibacterial, antifungal and antiproliferative agents. 41 This evoked us to develop novel ketolides containing tetrazole group with the hope that they could improve their potencies against susceptible and resistant pathogens.…”