Showing: 7 from total: 7 publications
1. Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?
Mesiti, F ; Gaspar, A ; Chavarria, D ; Maruca, A ; Rocca, R ; Martins, EG ; Barreiro, S ; Silva, R ; Fernandes, C ; Gul, S ; Keminer, O ; Alcaro, S ; Borges, F
in JOURNAL OF MEDICINAL CHEMISTRY, 2021, ISSN: 0022-2623,  Volume: 64, 
Article,  Indexed in: crossref, wos 
Abstract 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.

2. The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease
Mesiti, F ; Chavarria, D ; Gaspar, A ; Alcaro, S ; Borges, F
in EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2019, ISSN: 0223-5234,  Volume: 181, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.

3. Microencapsulation of caffeic acid phenethyl ester and caffeic acid phenethyl amide by inclusion in hydroxypropyl-beta-cyclodextrin
Garrido, EMPJ ; Cerqueira, AS ; Chavarria, D ; Silva, T ; Borges, F ; Garrido, JMPJ
in FOOD CHEMISTRY, 2018, ISSN: 0308-8146,  Volume: 254, 
Article,  Indexed in: crossref, scopus, wos 
Abstract Caffeic acid phenethyl ester (CAPE) is a bioactive polyphenolic compound obtained from propolis extract. Although it has a broad therapeutic potential, the bioavailability of CAPE is limited, due to reduced solubility and poor plasmatic stability. Efforts to reduce these pharmacokinetic drawbacks resulted in the synthesis of caffeic acid phenethyl amide (CAPA). Cyclodextrins have been proved as promising excipients for the formulation of active ingredients. Herein, we report the inclusion complexation behavior and binding ability of CAPE and CAPA with hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The supramolecular interactions were examined through UV and FTIR spectroscopy, DSC, H-1 NMR and 2D ROESY. The CAPE/HP-beta-CD and CAPA/HP-beta-CD inclusion complexes stability constants were determined to be, respectively, 2911.6 and 584.6 M-1 in water and 2866.2 and 700.1 M-1 at physiological pH. The aqueous solubility increased notably, proving that HP-beta-CD can be potentially useful to improve the biological, chemical and physical properties of CAPE and CAPA.

4. Correction to: Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors (Journal of Medicinal Chemistry (2016) 59 (5879-5893) DOI: 10.1021/acs.jmedchem.6b00527)
Reis, J ; Cagide, F ; Chavarria, D ; Silva, T ; Fernandes, C ; Gaspar, A ; Uriarte, E ; Remião, F ; Alcaro, S ; Ortuso, F ; Borges, F
in Journal of Medicinal Chemistry, 2018, ISSN: 0022-2623,  Volume: 61, 
Correction,  Indexed in: crossref, scopus 
Abstract N-(3′-Chlorophenyl)-4-oxo-4H-chromene-3-carboxamide, compound 20 (IC 50 = 403 pM), acts as noncompetitive reversible inhibitor, and N-(3′,4′-dimethylphenyl)-4-oxo-4Hchromene- 3-carboxamide, compound 27 (IC 50 = 669 pM), acts as competitive reversible inhibitor. Therefore, the following corrections to the above article are as follows. Page 5879. In the abstract, line 9, "N-(3′-chlorophenyl)-4- oxo-4H-chromene-3-carboxamide (20)" should be "N-(3′- chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (27)". Page 5884. In Figure 3 "mechanism of hMAO-B inhibition by chromones 20 (A) and 27 (B)" should be "mechanism of hMAO-B inhibition by chromones 27 (A) and 20 (B)". Page 5885. Line 4, "Concerning compound 20" should be "Concerning compound 27". Page 5885. Line 6, "different concentrations of 20" should be "different concentrations of 27". Page 5885. Line 8, "As for compound 27" should be "As for compound 20". Page 5885. Line 11, "for different concentrations of compound 27" should be "for different concentrations of compound 20". Page 5885. Line 19, should be "Chromones 27 (Figure 3A) and 20 (Figure 3B)" instead of "Chromones 20 (Figure 3A) and 27 (Figure 3B)". Page 5885. Lines 23-26, should be "27 (IC 50 = 0.67 nM) displayed IC 50 and Ki values within the picomolar range, and compound 20 (IC 50 = 0.40 nM), as a noncompetitive inhibitor, also showed a Ki extremely close to its IC 50 " instead of "20 (IC 50 = 0.40 nM) displayed IC 50 and Ki values slightly different but within the picomolar range, and compound 27 (IC 50 = 0.67 nM), as a noncompetitive inhibitor, showed a Ki equal to its IC 50 ." Page 5887. In the Conclusion, line 12, "competitive IMAOB" should be "noncompetitive IMAO-B". Page 5887. In the Conclusion, line 14, "a noncompetitive IMAO-B" should be "a competitive IMAO-B". © 2018 American Chemical Society.

5. Discovery of the first A(1) adenosine receptor ligand based on the chromone scaffold
Cagide, F ; Reis, J ; Gaspar, A ; Chavarria, D ; Kachler, S ; Klotz, KN ; Gomes, LR ; Low, JN ; Vilar, S ; Hripcsak, G ; Borges, F
in RSC ADVANCES, 2016, ISSN: 2046-2069,  Volume: 6, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The first potent and selective hA(1)AR ligand based on the chromone scaffold is reported in this work. Receptor-driven molecular modeling studies provide valuable information about the molecular interactions responsible for the high affinity of N-(2-nitrophenyl)-4-oxo-4H-chromene-2-carboxamide to the hA(1)AR (K-i = 0.219 mu M) and reinforce the crucial role of AR affinity of the amide linker located at C-2 of the pyrone ring.

6. Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors
Reis, J ; Cagide, F ; Chavarria, D ; Silva, T ; Fernandes, C ; Gaspar, A ; Uriarte, E ; Remiao, F ; Alcaro, S ; Ortuso, F ; Borges, F
in JOURNAL OF MEDICINAL CHEMISTRY, 2016, ISSN: 0022-2623,  Volume: 59, 
Article,  Indexed in: crossref, scopus, wos 
Abstract The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the gamma-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.

7. Navigating in chromone chemical space: discovery of novel and distinct A(3) adenosine receptor ligands
Cagide, F ; Gaspar, A ; Reis, J ; Chavarria, D ; Vilar, S ; Hripcsak, G ; Uriarte, E ; Kachler, S ; Klotz, KN ; Borges, F
in RSC ADVANCES, 2015, ISSN: 2046-2069,  Volume: 5, 
Article,  Indexed in: crossref, scopus, wos 
Abstract One of the major hurdles in the development of safe and effective drugs targeting G-protein coupled receptors (GPCRs) is finding ligands that are highly selective for a specific receptor subtype. The search for novel compounds with therapeutic value by targeting the A(3) adenosine receptor (A(3)AR) is still in its early stages. The increasing knowledge about the biological, physiological and pathological role of the A(3)AR subtype was accompanied by the design and development of the A(3)AR ligands, but the particular role of A(3)AR agonists and antagonists is still an open issue. Among the large variety of chemical classes screened towards ARs flavonoids have been indicated as remarkable A(3)AR antagonists. However, the search of A(3)AR ligands based on this framework seems to be discontinued. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on the chemical core of flavonoids, the chromone scaffold. The ongoing research has shown that chromone-2-phenylcarboxamide derivatives display a remarkable preference for hA(3)AR. In this work we report stimulating results, supported by A(2A)/A(3) molecular docking simulations and structure-affinity-relationship (SAR) studies by which N-(4,5-methylthiazol-2-yl)-4-oxo-4H-chromene-2-carboxamide (compound 31) emerged as the most potent and selective compound, displaying an hA(3) K-i of 167 nM and a selectivity ratio of 590 vs. the hA(1) and 480 vs. the hA(2A)AR subtypes. The chromone-based ligand was obtained by a simple synthetic approach and will enter in a lead optimization program to enhance its potency and drug-like properties.