Computationally assisted lead optimization of novel potent and selective mao-b inhibitors

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and-B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders

Comparative single dose pharmacokinetics and metabolism of racemic primaquine and its enantiomers in human volunteers

Primaquine (PQ) is a racemic drug used in treatment of malaria for six decades. Recent studies suggest that the two enantiomers of PQ are differentially metabolized in animals, and this results in different pharmacological and toxicological profiles. The current study characterizes the pharmacokinetic (PK) properties, metabolism and tolerability of the individual enantiomers of PQ in healthy human volunteers with normal glucose-6-phosphate dehydrogenase (G6PD) activity. Two cohorts (at two dose levels), each with 18 subjects, participated in three study arms in a crossover fashion: a single dose of the (−)-R enantiomer (RPQ), a single dose of the (+)-S enantiomer (SPQ), and a single dose of racemic PQ (RSPQ). PQ and its key metabolites carboxyprimaquine (cPQ) and PQ-N-carbamoyl glucuronide (PQ-N-CG) were analyzed. Clear differences were observed in PK and metabolism of the two enantiomers. Relative PQ exposure was higher with SPQ as compared to RPQ. PQ maximum plasma concentration (Cmax) and area under the plasma concentration-time curve were higher for SPQ, while the apparent volume of distribution and total body clearance were higher for RPQ. Metabolism of the two enantiomers showed dramatic differences: plasma PQ-N-CG was derived solely from SPQ, while RPQ was much more efficiently converted to cPQ than was SPQ. Cmax of cPQ and PQ-N-CG were 10 and 2 times higher, respectively, than the parent drugs. The study demonstrates that the PK properties of PQ enantiomers show clear differences, and metabolism is highly enantioselective. Such differences in metabolism suggest potentially distinct toxicity profiles in multi-dose regimens, especially in G6PD-deficient subjects

Enantioselective interactions of anti-infective 8-aminoquinoline therapeutics with human monoamine oxidases a and b

8-Aminoquinolines (8-AQs) are an important class of anti-infective therapeutics. The monoamine oxidases (MAOs) play a key role in metabolism of 8-AQs. A major role for MAO-A in metabolism of primaquine (PQ), the prototypical 8-AQ antimalarial, has been demonstrated. These investigations were further extended to characterize the enantioselective interactions of PQ and NPC1161 (8-[(4-amino-1-methylbutyl) amino]-5-[3, 4-dichlorophenoxy]-6-methoxy-4-methylquinoline) with human MAO-A and-B. NPC1161B, the (R)-(−) enantiomer with outstanding potential for malaria radical cure, treatment of visceral leishmaniasis and pneumocystis pneumonia infections is poised for clinical development. PQ showed moderate inhibition of human MAO-A and-B. Racemic PQ and (R)-(−)-PQ both showed marginally greater (1.2-and 1.6-fold, respectively) inhibition of MAO-A as compared to MAO-B. However, (S)-(+)-PQ showed a reverse selectivity with greater inhibition of MAO-B than MAO-A. Racemic NPC1161 was a strong inhibitor of MAOs with 3.7-fold selectivity against MAO-B compared to MAO-A. The (S)-(+) enantiomer (NPC1161A) was a better inhibitor of MAO-A and-B compared to the (R)-(−) enantiomer (NPC1161B), with more than 10-fold selectivity for inhibition of MAO-B over MAO-A. The enantioselective interaction of NPC1161 and strong binding of NPC1161A with MAO-B was further confirmed by enzyme-inhibitor binding and computational docking analyses. Differential interactions of PQ and NPC1161 enantiomers with human MAOs may contribute to the enantioselective pharmacodynamics and toxicity of anti-infective 8-AQs therapeutics

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana)

© 2019 John Wiley & Sons Ltd Background: Bodybuilding supplements can cause a profound cholestatic syndrome. Aim: To describe the drug-Induced liver injury network\u27s experience with liver injury due to bodybuilding supplements. Methods: Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. Results: Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R \u3e 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. Conclusions: Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies

Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1-3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4-6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50\u27s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and \u3e292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders

Promising selective MAO-B inhibition by sesamin, a lignan from Zanthoxylum flavum stems

© 2020 The Author(s) Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of Zanthoxylum flavum stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from Z. flavum for the first time). Compound 3 (sesamin) exhibited potent selective MAO-B inhibition (IC50 value of 1.45 ± 0.05 µM) which reported herein for the first time. Compound 2 showed selective MAO-A inhibition activity, compound 5 exhibited good trypanocidal activity, and compound 7 displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (Ki: 0.473 ± 0.076 μM). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality

Isolation and Biological Evaluation of Prenylated Flavonoids from Maclura pomifera

Phytochemical analysis of the ethanolic extract of Maclura pomifera fruits yielded four new compounds (I–IV) along with eleven known compounds (V–XV). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with δ and μ opioid receptors (−49.7 and −53.8% displacement, resp.). Compound I was found to be possibly allosteric for κ and μ opioid receptors (−88.4 and −27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound II exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (V–VIII) exhibited prominent activity towards cannabinoid receptors: pomiferin (V) (IC50 of 2.110 and 1.318 μM for CB1 and CB2, resp.), auriculasin (VI) (IC50 of 8.923 μM for CB1), warangalone (VII) (IC50 of 1.670 and 4.438 μM for CB1 and CB2, resp.), and osajin (VIII) (IC50 of 3.859 and 7.646 μM for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin (VI) (IC50 of 1.91 and 45.98 μM for MAO-B and MAO-A, resp.)

Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration

Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects

Metabolic clustering of a core collection of Indian ginseng Withania somnifera Dunal through DNA, isoenzyme, polypeptide and withanolide profile diversity

Withania somnifera is one of the most important medicinal plants of Ayurveda and finds extensive uses in Indian traditional herbal preparations. In this investigation, selected accessions of the plant were examined for diversity through RAPDs, isoenzymes, polypeptide polymorphism and withanolide profiles. The accessions clustered together with respect to their characteristic profile of major withanolides and represented withaferin A, withanone, withanolide D or withanolide A rich groups. This level of phytochemical diversity as discrete chemotypes is widest and is being first ever documented to occur in Indian population of the plant