Potent Monoamine Oxidase Inhibitors Research Articles

Synthesis and evaluation of 2-methylbenzothiazole derivatives as monoamine oxidase inhibitors

AbstractNeurodegenerative disorders are caused by the progressive death of neuronal cells in specific regions of the brain and spinal cord. The most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. The inhibition of enzymes that metabolise neurotransmitter amines is an important approach in the treatment of these disorders and monoamine oxidase (MAO) B inhibitors have thus been used for the treatment of Parkinson’s disease. Inhibitors of the MAO-A isoform, in turn, are used clinically for the treatment of affective (e.g., major depression) and anxiety disorders. Recent studies have shown that benzothiazole derivatives act as potent MAO inhibitors. Based on these findings, the present study group synthesised thirteen 2-methylbenzo[d]thiazole derivatives and evaluated their in vitro MAO inhibition properties. The results showed that the benzothiazole derivatives were potent and selective inhibitors of human MAO-B, with all compounds exhibiting IC50 values < 0.017 µM. The most potent MAO-B inhibitor (4d) had an IC50 value of 0.0046 µM, while the most potent MAO-A inhibitor (5e) had an IC50 value of 0.132 µM. It may be concluded that active benzothiazole derivatives may serve as potential leads for the development of MAO inhibitors for the treatment of neuropsychiatric and neurodegenerative disorders.

Discovery of C-3 isoxazole substituted thiochromone S,S-dioxide derivatives as potent and selective inhibitors for monoamine oxidase B (MAO-B)

Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency.

Investigation of the monoamine oxidase inhibition properties of benzoxathiolone derivatives

The treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease represent significant challenges in healthcare. Enzymes that metabolise neurotransmitter amines are important drug targets for these disorders and inhibitors of these enzymes have played key roles as therapeutic agents. For example, inhibitors of monoamine oxidase (MAO) A have been used for decades as antidepressant agents and act by inhibiting the central metabolism of serotonin and noradrenaline, while MAO-B inhibitors conserve central dopamine supply and have been used to treat Parkinson’s disease. Literature reports that benzoxathiolone derivatives act as potent MAO inhibitors with specificity for the MAO-B isoform. To expand on these findings, the present study synthesised series of benzoxathiolone derivatives and investigated their human MAO inhibition properties. The results showed that the benzoxathiolone derivatives were potent MAO inhibitors, with the most potent compounds exhibiting IC50 values of 0.083 and 0.086 µM (4d and 5e) and 0.0069 and 0.0066 µM (3a and 3b) for MAO-A and MAO-B, respectively. Compounds 4d and 5e are significantly more potent MAO-A inhibitors compared to those reported previously. It may be concluded that benzoxathiolone derived compounds may act as future leads for the development of new treatments for depression and Parkinson’s disease.Graphical

Coumarin derivatives as inhibitors of d-amino acid oxidase and monoamine oxidase

d-Amino acid oxidase (DAAO) oxidises d-amino acids to ultimately produce the corresponding α-keto acids. The DAAO substrate, d-serine, is a co-agonist at NMDA receptors, while NMDA receptor hypo-function has been implicated in the pathophysiology of schizophrenia. Through the modulation of d-serine levels, the inhibition of DAAO represents a strategy to increase NMDA receptor function, and thus a potential treatment for schizophrenia. Literature reports that 3-hydroxycoumarin is a potent inhibitor of DAAO and represents an ideal lead for the development of novel DAAO inhibitors. Based on this, the present study investigated DAAO inhibition by a series of synthetic and commercially available coumarin derivatives. Due to structural similarity to coumarin, a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives has also been included in this study. The results show that among 37 compound evaluated, four inhibit porcine kidney DAAO with IC50 < 10 µM. The most potent inhibitors are 3,7-dihydroxycoumarin and 6,7-dihydroxycoumarin with an IC50 values of 0.167 and 0.224 µM, respectively. These values are an improvement on that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.88 µM). Coumarin compounds are also known to inhibit the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson’s disease. As DAAO and MAO are flavoenzymes, off-target inhibition may occur. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibit the recombinant human MAOs with IC50 < 0.1 µM, with the most potent MAO-A and MAO-B inhibitors exhibiting IC50 values of 0.033 and 0.012 µM, respectively. This is significantly more potent than the reference inhibitors, curcumin, isatin and toloxatone. This study concludes that active DAAO and MAO inhibitors may serve as novel leads for the design of compounds that may find future application in the treatment of neuropsychiatric (e.g. schizophrenia, depression) and neurodegenerative disorders (e.g. Parkinson’s disease).

(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

Potent and Selective Inhibitors of Human Monoamine Oxidase A from an Endogenous Lichen Fungus Diaporthe mahothocarpus.

Using 126 endogenous lichen fungus (ELF) extracts, inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) were evaluated. Among them, extract ELF29 of the endogenous fungus Diaporthe mahothocarpus of the lichen Cladonia symphycarpia showed the highest inhibitory activity against hMAO-A. Compounds alternariol (AT), 5′-hydroxy-alternariol (HAT), and mycoepoxydiene (MED), isolated from the extract, had potent inhibitory activities against hMAO-A with IC50 values of 0.020, 0.31, and 8.68 µM, respectively. AT, HAT, and MED are reversible competitive inhibitors of hMAO-A with Ki values of 0.0075, 0.116, and 3.76 µM, respectively. The molecular docking studies suggested that AT, HAT, and MED had higher binding affinities for hMAO-A (−9.1, −6.9, and −5.6 kcal/mol, respectively) than for hMAO-B (−6.3, −5.2, and −3.7 kcal/mol, respectively). The relative tight binding might result from a hydrogen bond interaction of the three compounds with a Tyr444 residue in hMAO-A, whereas no hydrogen bond interaction was proposed in hMAO-B. In silico pharmacokinetics, the three compounds showed high gastrointestinal absorption without violating Lipinski’s five rules, but only MED showed high probability to cross the blood–brain barrier. These results suggest that AT, HAT, and MED are candidates for treating neuropsychiatric disorders, such as depression and cardiovascular disease.

Navigating into the Chemical Space of Monoamine Oxidase Inhibitors by Artificial Intelligence and Cheminformatics Approach.

The monoamine oxidase (MAO) enzyme class is a prevalent target for many neurodegenerative and depressive disorders. Even though scrutinization of many promising drugs for the treatment of MAO inhibition has been carried out in recent times, a conclusive structural requirement for potent activity needs to be developed. Numerous approaches have been examined for the identification of structural features for potent MAO inhibitors (MAOIs) that mainly involve an array of computational studies, synthetic approaches, and biological evaluation. In this paper, we have analyzed ∼2200 well-known MAOIs to expand perceptions in the chemical space of MAOIs. The physicochemical properties of the MAOIs disclosed a discernible hydrophobic feature making a bunch discrete from the central nervous system (CNS) acting drugs, as exposed using the principal component analysis (PCA). The Murcko scaffold structure study revealed unfavorable and favorable scaffold structures, in both data sets, with the highest biological activity shown by the 3-phenyl-2H-chromen-2-one scaffold. This scaffold showed a polypharmacological effect. R-group disintegration and automatic structure–activity relationship (SAR) study resulted in identification of substructures responsible for the inhibitory bioactivity of the MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant biological activity was detected by simple molecular conversion in the chemical compound structure. In addition, we used the machine learning tool to generate a hypothesis wherein pyrazole, benzene ring, and amide containing structural functionalities can exhibit potential biological activities. This hypothesis revealed that CNS target drugs, C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and C43644, could be repurposed as valuable candidates for the MAO-B enzyme. For researchers, this study will bring new perceptions in the discovery and development of MAOIs and direct lead and hit optimization for the progress of small molecules beneficial for MAO-targeting associated diseases.

Biphenylpiperazine Based MAO Inhibitors: Synthesis, Biological Evaluation, Reversibility and Molecular Modeling Studies

In this study, 21 new 1,4-biphenylpiperazine derivatives were designed, synthesized and evaluated as monoamine oxidase (MAO) inhibitors by in vitro fluorometric method. All these compounds exhibited inhibitory activity against hMAO enzymes, 17 analogues of them showed selectivity towards hMAO-B over hMAO-A enzyme. Compound 20 exhibited the best activity and selectivity towards hMAO-B with IC50 value of 53 nM and selectivity index of 1122 folds over MAO-A, compared to the reference drugs rasagiline (IC50 = 66 nM) and selegiline (IC50 = 40 nM). Kinetic study and reversibility test of the most potent compound (20) revealed that it is reversible and mixed competitive inhibitor (Ki value is 17 nM for the inhibition of hMAO-B). Compound 20 was evaluated against normal NIH/3T3 mouse embryonic fibroblast cell lines and it was found that it is non-cytotoxic at its effective concentration against hMAO-B. Moreover, compound 20 and the most potent compounds have acceptable ADME properties and good pharmacokinetics profiles. Molecular docking simulations were performed for explanation and elucidation for the biological activity of compounds 19 and 20. Accordingly, 1,4- biphenylpiperazine derivatives can be considered as a promising lead to produce more potent and safer MAO inhibitors for management of various neurological disorders.

Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.

Monoamine Oxidase Inhibitory Effects of Medicinal Plants in Management of Alzheimer's Disease

Alzheimer's disease is the most common progressive neurodegenerative disorder that effects large population of society especially elderly people. Environmental and/or genetic factors contribute Alzheimer's disease to become a pivotal health problem but this relationship remains ambiguous. Globally growing prevalence of Alzheimer’s disease requires to understand cellular pathways that lead to Alzheimer’s disease and to develop new strategies for prevention and treatment. Elevated monoamine oxidase (MAO) enzymes activity with ages is associated with etiology of Alzheimer's disease. Inhibition of monoamine oxidase enzyme can protect from neuronal damage, thus it become one of the key pathway for management of Alzheimer’s disease. Using bioactive compounds from medicinal plants as potential monoamine oxidase inhibitors might be a better solution considering undesired side effects of synthetic drugs on human body. The purpose of this review is to implicate the importance of pharmacophore analysis which explains pharmacological properties of medicinal plants and interaction of bioactive compound from plants with MAO enzyme.

Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact.

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Selected 1,3-Benzodioxine-Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors.

Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3-benzodioxine-containing chalcones (CD3, CD8 and CD10), and their inhibitory activities against MAO-A, MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO-B with an IC50 value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non-selectively inhibited MAO-A (IC50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC50 values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the Ki values of CD8 for MAO-A and MAO-B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood-brain barrier permeabilities, and non-toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO-B was higher than that for MAO-A. The results indicate that CD8 is a potent non-selective MAO inhibitor, and CD10 is an effective selective MAO-B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual-targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.

Design, Synthesis and Evaluation of O‐Pentyne Substituted Diphenylpyrimidines as Monoamine Oxidase and Acetylcholinesterase Inhibitors

AbstractAlzheimer's disease (AD) is a multifactorial neurological disorder and single target directed drugs have been found ineffective in the retardation or reversal of disease state. In last few years, multi‐targeting agents are being explored as drug strategy for the effective treatment of AD. A series of (4‐(pent‐4‐yn‐1‐yloxy)phenyl)‐2‐phenylpyrimidine derivatives has been synthesized and evaluated against monoamine oxidase (MAO) and acetylcholinesterase (AChE) enzymes. Most of the synthesized compounds were found to be potent inhibitors of MAO−A, MAO−B and AChE enzymes with IC50 values in low micromolar range. In the series, BD‐13 and BD‐14 were found to be the most potent dual inhibitors of MAO−A and AChE enzymes. BD‐13 showed MAO−A and AChE inhibition with IC50 values of 0.78±0.12 μM and 2.84±0.19 μM, respectively. Similarly, BD‐14 showed potent inhibition activities against MAO−A and AChE enzymes with IC50 values of 0.75±0.04 μM and 2.19±0.06 μM, respectively. In reversibility studies, BD‐13 and BD‐14 were found to be reversible inhibitors of both MAO−A and AChE enzymes. In the cytotoxicity studies, BD‐13 and BD‐14 were found to be non‐toxic to the SH‐SY5Y cells. In the molecular dynamic simulation studies of 30 ns, both the potent compounds were found to be thermodynamically stable in the active sites of MAO−A and AChE. Thus, BD‐13 and BD‐14 can be used as lead compounds for the development of more potent compounds for the effective treatment of Alzheimer's disease.

Quantitative Structure-Activity Relationship (QSAR) Studies for the Inhibition of MAOs.

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson's disease, and Alzheimer's disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.

Natural based piperine derivatives as potent monoamine oxidase inhibitors: an in silico ADMET analysis and molecular docking studies

Neurodegenerative disorders follow numerous pathological ways concerning overexpression of monoamine oxidase and formation of reactive oxygen species. The computational design of the piperine derivatives has given the significant MAO inhibitors with considerable antioxidant potential. Molecular docking provided the mechanistic insight of the compounds within the hMAO active site. In the current study we have prepared a series of compounds related to piperine and investigated them through monoamine oxidase A and B assay and evaluated the free radical scavenging activity. The synthesized compounds were analyzed by using in silico techniques within the active site of MAO and the ADMET properties were also calculated. The results obtained in this study indicated the interesting therapeutic potential of some compounds such as 7and 17c as most promising hMAO-A inhibitors whereas compounds 15, 5 and 17b were found as hMAO-B inhibitors. Moreover, we assessed the antioxidant potential of the piperine analogues and compounds 5, 17b, and 7 showed very modest antioxidant activity against DPPH and H2O2 radicals. The outcome of the study indicating that the piperine related derivatives are found as considerable MAO inhibitors and antioxidants. Moreover, the SAR structure activity relationships are depicting the structural features required for the MAO inhibition. In case of MAO activity, good correlations were found among the calculated and experimental results.

Optimization of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives as inhibitors of monoamine oxidase.

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC50 value of 0.006 μM while the most potent MAO-B inhibitor exhibits an IC50 value of 0.058 μM. Interestingly, an N-oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 μM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.

MON-429 Malady or Remedy? Hypertensive Crisis in a Young Woman with Use of St. John's Wort for Depression

Introduction St. John’s Wort (Hypericum perforatum) is a commonly available herbal supplement often used for depression and other mood disorders.1 Described below is the case of a young woman who presented with Hypertensive crisis in the setting of self-treatment of depression with St. John’s wort (SJW). Case A 39-year-old female with past history of migraines presented with blurry vision and frontal headache of 1 week duration. She was noted to have significant papilledema and blood pressure of 209/115mm hg and started on nitroprusside infusion. Physical exam was significant for relative afferent pupillary defect and also a right inferior nasal visual field cut. Work up for secondary causes of hypertension showed urine metanephrine level of 194 mcg/g/cr (32-134 mcg/g cr). Renin and aldosterone levels were not consistent with hyperaldosteronism. MRI showed Flattening of the pituitary gland and the posterior sclerae along with enlargement of the subarachnoid space around the optic nerves. Findings were suggestive of Idiopathic intracranial hypertension. Lumbar puncture showed an opening pressure of 42 cm and closing pressure of 21cm CSF. After management of hypertensive emergency in ICU, she was started on acetazolamide for intracranial hypertension and labetalol for hypertension. History of use of St John’s wort was elicited on follow up with endocrinology. Also, in the last 2 months prior to admission she could not recollect a history of excessive amounts of alcohol or cheese intake. She was asked to repeat work up after stopping SJW and labetalol being switched to amlodipine. Plasma metanephrine level repeated 2 weeks later was <25 pg/ml. Blood pressure checked 2 months after stopping SJW was noted to be 126/86 mm hg on amlodipine 10mg and Lisinopril 5mg daily. Discussion The temporal relation of SJW and hypertensive emergency and the normalization of blood pressure and plasma metanephrine levels after stopping SJW in our patient is compelling. SJW is described to act as a potent monoamine oxidase inhibitor and MAO inhibitors with excessive intake of tyramine containing foods like cheese and wine can cause hypertensive crisis. 1 The potential excess tyramine containing foods in the presence of SJW may have played a role. Also use of MAO inhibitors with other SSRI can cause Serotonin syndrome2, however our patient did not have features of serotonin syndrome. Further studies are required to elucidate the side effects of SJW and to educate the general population about such potential dangerous effects of this commonly used herbal remedy. References 1 Patel S et al. Hypertensive crisis associated with St. John’s Wort. The American Journal of Medicine, Volume 112, Issue 6, 507 - 508 2 Lawvere S. St. John’s Wort. American Family Physician. 2005 Dec 1;72(11):2249-2254.

In Silico Design, Synthesis of Hybrid Combinations: Quercetin Based MAO Inhibitors with Antioxidant Potential.

Monoamine oxidase (MAO) is a critical target used for the cure of neuropsychological diseases. A series of quercetin based derivatives was designed, synthesized, and evaluated as novel multifunctional agents against monoamine oxidase A and B with antioxidant potential. Hybrid derivatives based on quercetin were synthesized and screened for hMAO inhibition along with antioxidant activity. Molecular docking was performed to explicate the rationale of the different MAO (IC50) values and to explain the presence of inhibitory activity against specificity, respectively. The results of in vitro hMAO inhibition showed that compound 8a, 6c, and 4 were found as potent hMAO-A inhibitors whereas compounds 6b, 6a, and 6d were observed as potent hMAO-B inhibitors. The DPPH radical scavenging activity showed that compounds 6b, 6a, and 4 exhibited a promising antioxidant potential with IC50 values 5.931±0.007, 6.421±0.037, and 8.516±0.098 respectively. Moreover, the compound 6b, 6a, and 4 exhibited remarkable H2O2 scavenging potential with IC50 values 05.80±0.004 µM, 06.20±0.009 µM, and 07.66±0.009 µM respectively. The results of docking studies were found in good correlation with experimental MAO inhibition studies. Moreover, the mechanistic insight into the docking poses was also explored by binding interactions of quercetin based derivatives inside the dynamic site of hMAO-A and hMAO-B. It was also noticed that the potent MAO inhibitors were also acting as better antioxidants as evaluated through DPPH radical scavenging activity and H2O2 radical scavenging assay.

Synthesis, X-ray crystal and monoamine oxidase inhibitory activity of 4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine 5,5-dioxides: In vitro studies and docking analysis

We report the synthesis and biological evaluation of two new series of 2-amino-6-benzyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides and 2-amino-6-methyl-4-phenyl-4,6-dihydrobenzo[c]pyrano[2,3-e][1,2]thiazine-3‑carbonitrile 5,5-dioxides. The synthetic methodology involves a multistep reaction starting with methyl anthranilate which was coupled with methane sulfonyl chloride. The product of the reaction was subjected to N-benzylation and N-methylation reactions followed by ring closure with sodium hydride resulting in the formation of respective 2,1-benzothiazine 2,2-dioxides. These 2,1-benzothiazine precursors were subjected to multicomponent reaction with malononitrile and substituted benzaldehydes for the synthesis of two new series of pyranobenzothiazines (6a–r and 7a–r). The synthesized compounds were screened as selective inhibitors of monoamine oxidase A and monoamine oxidase B. The in vitro results suggested that compound 6d and 7q are the selective inhibitors of monoamine oxidase A, however, the selective and potent inhibitors of monoamine oxidase B included compounds 6h and 7r. Moreover, some dual inhibitors were noticed like 7l having more inhibitory activity towards both the isozymes. Moreover, the binding modes of the selective and potent inhibitors of monoamine oxidase A and B were investigated by molecular docking analysis. The results suggested that the synthetic derivatives may be potential towards the monoamine oxidase isozymes.

Exploration of Umbelliferone Based Derivatives as Potent MAO Inhibitors: Dry vs. Wet Lab Evaluation.

Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson's disease. We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 µM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044µM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.