Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies

Chavarria, Daniel; Fernandes, Carlos; Silva, Vera; Silva, Cátia; Gil-Martins, Eva; Soares, Pedro; Silva, Tiago; Silva, Renata; Remião, Fernando; Oliveira, Paulo J.; Borges, Fernanda

doi:10.1016/j.ejmech.2019.111770

Cited by 31 publications

(15 citation statements)

References 55 publications

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“…The evaluation of i- h MAOs ( 2 – 5 , 7 – 10 , 14 – 17 , 20 – 25 , and 30 and 31 ) was performed using a spectrophotometric assay using kynuramine as a substrate and recombinant h MAO-A and h MAO-B isoforms. , Since IC 50 values of Crom-1 and Crom-2 reported by Reis et al . were determined using the Amplex Red assay, their activity was reassessed under our experimental conditions.…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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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 IC 50 = 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.

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Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2021

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“…HepG2 cellular density was not affected by incubation with 1 or 2 but significantly decreased upon exposure to 3, in a concentration-dependent manner. In fact, while the lowest concentration of 3 did not have a cytotoxic effect on the cells (12.5 μM, 87.99 ± 2.10%), higher concentrations were showen to be cytotoxic, with the cell density gradually decreasing as the administered concentration increased (25 μM, 83.65 ± 3.37%; 50 μM, 82.38 ± 3.26%; 100 μM, 79.27 ± 2.36%), with <85% being considered as a cutoff value for cytotoxicity 48 (Figure 7a).…”

Section: Measurement Of Intracellularmentioning

confidence: 99%

Coordination Compounds As Multi-Delivery Systems for Osteoporosis

Barbosa

Pinto

Barreiro

et al. 2021

ACS Appl. Mater. Interfaces

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Osteoporosis therapies leveraging bisphosphonates and mineral components (e.g., magnesium, calcium, and strontium) have been raising attention because of their potential for managing this ever-growing disease. The administration of multicomponent therapeutics (combined therapy) in elderly patients is complex and suffers from low patient adherence. Herein, we report an all-in-one combination of four antiosteoporotic components into a new family of coordination complexes: [M2(H4alen)4(H2O)2]·1.5H2O [where M2+ = Mg2+ (1), (Mg0.535Ca0.465)2+ (2) and (Mg0.505Ca0.450Sr0.045)2+ (3)]. These solid-state complexes were prepared, for the first time, through microwave-assisted synthesis. It is demonstrated that the compounds are capable of releasing their antiosteoporotic components, both in conditions that mimic the path along the gastrointestinal tract and in long periods under physiological conditions (pH ∼7.4). More importantly, when administered in low concentrations, the compounds did not elicit a cytotoxic effect toward liver, kidney, and osteoblast-like cell lines. Besides, it is important to highlight the unique coordination complex with four bone therapeutic components, [(Mg0.505Ca0.450Sr0.045)2(H4alen)4(H2O)2]·1.5H2O (3), which significantly promoted osteoblast metabolic activity up to ca. 1.4-fold versus the control group. These findings bring this type of compounds one-step closer to be considered as an all-in-one and more effective treatment for managing chronic bone diseases, prompting further research on their therapeutic properties.

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“…In particular, compound 15 ( 8 in Figure 2 ) showed a high inhibition rate at MAO-B and a high value of the MAO-B over the MAO-A selectivity index ( Table 1 ). The competitive mechanism of MAO-B inhibition of piperine derivatives was indicated in kinetic studies [ 84 ]. The multi-target approach for drug design against PD was exploited by Tao et al, resulting in discovery of derivatives of coumarin Mannich base with combined activity against MAO-B and neuroinflammation.…”

Section: Recent Reports Of Novel Agents Against Parkinson’s Diseasementioning

confidence: 99%

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

et al. 2021

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Parkinson’s disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease. An increasing understanding of Parkinson’s pathogenesis and the discovery of new molecular targets pave the way to develop new therapeutic agents. The use and selection of appropriate cell and animal models that better reflect pathogenic changes in the brain is a key aspect of the research. In addition, computer-assisted drug design methods are a promising approach to developing effective compounds with potential therapeutic effects. In light of the above, in this review, we present current approaches for developing new drugs for Parkinson’s disease.

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Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies

Cited by 31 publications

References 55 publications

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

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

Coordination Compounds As Multi-Delivery Systems for Osteoporosis

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

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