The Synthesis and Evaluation of C7‐Substituted α‐Tetralone Derivatives as Inhibitors of Monoamine Oxidase

Based on a previous report that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7‐substituted α‐tetralone derivatives. Arylalkyloxy substitution on C7 of the α‐tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase‐B isoform with all compounds possessing IC₅₀ values in the submicromolar range (0.00089–0.047 μm ). The C7‐substituted α‐tetralones also were highly potent monoamine oxidase‐A inhibitors with thirteen (of fifteen) compounds possessing IC₅₀ values in the submicromolar range (0.010–0.741 μm ). The α‐tetralones were, however, in each instance selective for monoamine oxidase‐B over the monoamine oxidase‐A isoform. Dialyses of enzyme–inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase‐A inhibitor, inhibition of monoamine oxidase‐B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α‐tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7‐substituted α‐tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.     

Beyond Topoisomerase Inhibition: Antitumor 1,4‐Naphthoquinones as Potential Inhibitors of Human Monoamine Oxidase

Monoamine oxidase (MAO) action has been involved in the regulation of neurotransmitters levels, cell signaling, cellular growth, and differentiation as well as in the balance of the intracellular polyamine levels. Although so far obscure, MAO inhibitors are believed to have some effect on tumors progression. 1,4‐naphthoquinone (1,4‐NQ) has been pointed out as a potential pharmacophore for inhibition of both MAO and DNA topoisomerase activities, this latter associated with antitumor activity. Herein, we demonstrated that certain antitumor 1,4‐NQs, including spermidine‐1,4‐NQ, lapachol, and nor‐lapachol display inhibitory activity on human MAO‐A and MAO‐B. Kinetic studies indicated that these compounds are reversible and competitive MAO inhibitors, being the enzyme selectivity greatly affected by substitutions on 1,4‐NQ ring. Molecular docking studies suggested that the most potent MAO inhibitors are capable to bind to the MAO active site in close proximity of flavin moiety. Furthermore, ability to inhibit both MAO‐A and MAO‐B can be potentialized by the formation of hydrogen bonds between these compounds and FAD and/or the residues in the active site. Although spermidine‐1,4‐NQs exhibit antitumor action primarily by inhibiting topoisomerase via DNA intercalation, our findings suggest that their effect on MAO activity should be taken into account when their application in cancer therapy is considered.     

Substituted Xanthones as Selective and Reversible Monoamine Oxidase A (MAO-A) Inhibitors

l,3-Dihydroxy-2-methylxanthone (XI), its 4-chloro and 4-bromo derivatives (X1-C1 and Xl-Br), and 1 ,3-dihydroxy-4-methylxanthone were investigated for their inhibition activities toward MAO. A hyperbolic function was derived to fit the data and to calculate IC₅₀ values. The compounds proved to be reversible and selective inhibitors of MAO-A, with XI displaying the highest activity (IC₅₀ = 3.7 µM).     

Synthesis and screening of substituted 1,4‐naphthoquinones (NPQs) as antifilarial agents

Eleven amino‐substituted 1,4‐naphthoquinones were synthesized via the reaction of 1,4‐naphthoquinone with different primary and secondary mono‐ and diamines in the presence of dichloromethane ethanol (1:2) solvent at room temperature. All compounds were purified by flash column chromatography, characterized by TLC, HPLC, ¹³C‐NMR, ¹H‐NMR, and FT‐IR spectral analysis and were evaluated in vitro for antifilarial activity using adult bovine filarial worm Setaria digitata by assessing worm motility and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) reduction. Seven of the 11 compounds had macrofilaricidal activity with compounds 9 (2‐[(1,3‐dimethylbutyl) amino] naphthalene‐1,4‐dione) and 11 (2‐(4‐methylpiperazin‐1‐yl) naphthalene‐1,4‐dione) having maximum activity (ED₅₀ values of 0.91 and 1.2 µM, respectively, at 48 h). The effect of different substitutions on antifilarial activity is discussed. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

某儿童医院单胺氧化酶抑制剂使用情况及与其他药物相互作用调查

目的:了解与单胺氧化酶抑制剂(MAOIs)存在相互作用的儿科常用药物,提高药物合用的安全性、合理性。方法:通过查阅整理我院480种儿科常用药品说明书及中英文数据库,对涉及与MAOIs存在相互作用的药物及其结构进行分析,总结规律,并对我院2018年1-3月门诊使用呋喃唑酮片存在配伍禁忌的情况进行调查。结果:我院儿科常用药物,MAOIs 有6种,与MAOIs存在配伍禁忌的有38种,合用需减量的有17种,合用需药学监护的有13种,这些药物大部分具有“芳环-CH2-CH2-N-”或类似的结构。在统计的374例门诊处方开具呋喃唑酮片的患儿中,19.79%存在配伍禁忌。结论:医师开具处方时应尽量避免具有“芳环-CH2-CH2-N-”或类似结构的药物与MAOIs合用,药师在调剂时若碰到此类处方需做好用药交代,以避免或减少药物不良反应。     

Synthesis of Dimeric Quinazolin‐2‐one, 1,4‐Benzodiazepin‐2‐one,and Isoalloxazine Compounds as Inhibitors of Amyloid Peptides Association

The synthesis of dimeric compounds derived from quinazolin‐2‐one and 1,4‐benzodiazepin‐2‐one possessing a piperazine or homopiperazine spacer was investigated. In addition, a piperazine spacered bis‐isoalloxazine and a bis‐riboflavin compound were prepared and their ability to interrupt the association of prion proteins and Alzheimer‐specific Aβ peptides was investigated using a fast screening system based on flow cytometry. The bis‐isoalloxazine 14 was identified as a new lead structure.     

Monoamine oxidase inhibition and neuroprotection by N1‐propargylphenelzine

The ability of N¹‐propargylphenelzine and related N¹‐propargylhydrazines to inhibit monoamine oxidase‐A (MAO‐A) and ‐B (MAO‐B) and to prevent N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4)‐induced noradrenergic neurotoxicity was examined. N¹‐Propargylphenelzine strongly inhibited MAO‐A and MAO‐B in in vitro assays using rat brain or liver as the enzyme source. In ex vivo studies in rats, both intraperitoneal and oral administration of N¹‐propargylphenelzine strongly inhibited brain and liver MAO‐A and MAO‐B. The extent of ex vivo MAO inhibition and increased levels of noradrenaline and 5‐hydroxytryptamine by N¹‐propargylphenelzine was comparable to that of phenelzine. Unlike phenelzine, however, N¹‐propargylphenelzine did not elevate γ‐aminobutryic acid (GABA) concentrations in rat brain. A single intraperitoneal administration of N¹‐propargylphenelzine to mice, 1 week prior to sacrifice, reduced DSP‐4‐induced depletion of noradrenaline in the hippocampus. The brains of N¹‐propargylphenelzine‐treated mice from the DSP‐4 neurotoxicity experiments had normal MAO‐B activity, but MAO‐A was significantly inhibited; this was in contrast to animals that had received (–)‐deprenyl, who showed normal MAO‐A activity but a decrease of MAO‐B. The present results indicate that N¹‐propargylphenelzine may be a useful neuroprotective compound with a long‐term in vivo propensity to inhibit MAO‐A. Drug Dev. Res. 53:15–21, 2001. © 2001 Wiley‐Liss, Inc.     

Synthesis and Cytotoxic Evaluation of 6‐(3‐Pyrazolylpropyl) Derivatives of 1,4‐Naphthohydroquinone‐1,4‐diacetate

Several new 6‐(3‐pyrazolylpropyl) derivatives of 1,4‐naphthohydroquinone‐1,4‐diacetate (NHQ‐DA) have been prepared by chemical modifications of the Diels–Alder adduct of α‐myrcene and 1,4‐benzoquinone. All these new compounds and precursors have been evaluated in vitro for their cytotoxicity against cultured human cancer cells of MB‐231 breast‐adeno carcinoma, A‐549 lung carcinoma, and HT‐29 colon carcinoma. GI₅₀ values ranged in and below the micromolar concentration level.     

In Vitro Evaluation of Selected Benzimidazole Derivatives as an Antioxidant and Xanthine Oxidase Inhibitors

2‐Aryl‐1‐arylmethyl‐1H‐benzimidazole derivatives having different side chains on the structure were examined in vitro for their antioxidant abilities by 2,2‐diphenyl‐1‐picryl hydrazine radical scavenging activity, reducing ability, OH radical scavenging activity, inhibition of polyphenol oxidase and xanthine oxidase. Overall, with few exceptions, all the 2‐aryl‐1‐arylmethyl‐1H‐benzimidazoles showed moderate biological activity with all parameters examined. The 2‐aryl‐1‐arylmethyl‐1H‐benzimidazoles were found to be reactive toward 2,2‐diphenyl‐1‐picryl hydrazine radical and had considerable reducing ability, with significant xanthine oxidase inhibition. With few exceptions, all the compounds under study were found to possess moderate‐to‐poor OH radical scavenging activity and inhibited polyphenol oxidase significantly. These findings suggest that these 2‐aryl‐1‐arylmethyl‐1H‐benzimidazoles can be considered as potential antioxidant and xanthine oxidase inhibitory agents, those might be further, explored for the design of lead antioxidant and antigout drug candidates using in vivo trials.     

Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis

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Design of Novel β‐Carboline Derivatives with Pendant 5‐Bromothienyl and Their Evaluation as Phosphodiesterase‐5 Inhibitors

New derivatives with the tetrahydro‐β‐carboline‐imidazolidinedione and tetrahydro‐β‐carboline‐piperazinedione scaffolds and a pendant bromothienyl moiety at C‐5/C‐6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N‐substituents on the terminal ring (hydantoin/piperazinedione); the appropriate stereochemistry of C‐5/C‐6 derived from the aldehyde rather than C‐11a/C‐12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H‐loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC₅₀ values in the range of 0.16–5.4 µm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate.     

Synthesis and molecular modelling of novel substituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase-A inhibitors

This report describes novel pyrazoline derivatives investigated for their ability to selectively inhibit the activity of the A and B isoforms of monoamine oxidase. These new synthetic compounds proved to be reversible, potent, and selective inhibitors of monoamine oxidase-A rather than of monoamine oxidase-B, and are promising candidates to further advance drug discovery efforts. The most active compounds show inhibitory activity on monoamine oxidase-A in the 1.0x10(-8)-8.6x10(-9) M range. Moreover, it should be pointed out that for some compounds a high IC50>or=10(-9) M value is associated with a high A-selectivity (Selectivity Index monoamine oxidase-B/monoamine oxidase-A in the 10,000-12,500 range). Further insight to understand enzyme-inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms.     

Double-Blind Randomized Controlled Pilot Study of the Efficacy and Tolerability of Pirlindole,a Reversible Inhibitor of Monoamine Oxidase A,and Mianserin,in the Treatment of Depression

This double-blind randomized pilot study aimed to compare the efficacy and the tolerability of pirlindole (150–225 mg/day), a reversible inhibitor of monoamine oxidase A, and mianserin (60–90 mg/day) in the treatment of major depression. Forty patients were included in the trial (20 pirlindole and 20 mianserin) and 38 patients (18 pirlindole and 20 mianserin) completed the whole study (28 days of administration). Both treatments exhibited highly significant improvements in the Hamilton Depression Rating Scale score (HDRS), the Hamilton Anxiety Rating Scale score (HARS) and the Beck auto-evaluation scale score (BECK) from day 7 up to day 28. The evolution of the HDRS score in the two groups did not differ significantly. The evolution of the HARS and BECK scores taken separately and the evolution of the combined total score (HDRS + HARS + BECK) significantly differed between the two groups, pirlindole producing a significantly higher decrease than mianserin in the two separate scores on day 28 and on days 21 and 28 in the case of the combined total score. Two patients experienced adverse reactions, one in the pirlindole group complained of sleep disturbances and one in the mianserin group suffered from dry mouth. The results of this study attest to the efficacy and tolerability of pirlindole in the treatment of depression. © 1997 John Wiley & Sons, Ltd.