Showing: 10 from total: 54 publications
1.
4-Oxoquinolines and monoamine oxidase: When tautomerism matters
Mesiti, F
; Maruca, A
; Silva, V
; Rocca, R
; Fernandes, C
; Remiao, F
; Uriarte, E
; Alcaro, S
; Gaspar, A
; Borges, F
in EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2021, ISSN: 0223-5234, Volume: 213,
Article, Indexed in: crossref, scopus, wos
Abstract
4-Oxoquinoline derivatives have been often used in drug discovery programs due to their pharmacological properties. Inspired on chromone and 4-oxoquinoline chemical structure similarity, a small series of quinoline-based compounds was obtained and screened, for the first time, toward human monoamine oxidases isoforms. The data showed the N-(3,4-dichlorophenyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide 10 was the most potent and selective MAO-B inhibitor (IC50 = 5.30 +/- 0.74 nM and SI: >= 1887). The data analysis showed that prototropic tautomerism markedly influences the biological activity. The unequivocal characterisation of the quinoline tautomers was performed to understand the attained data. To our knowledge, there have been no prior reports on the characterisation of quinolone tautomers by 2D NMR techniques, namely by H-1-N-15 HSQC and H-1-N-15 HMBC, which are proposed as expedite tools for medicinal chemistry campaigns. Computational studies on enzyme-ligand complexes, obtained after MM-GBSA calculations and molecular dynamics simulations, supported the experimental data.
2.
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.
3.
The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide
Gomes, LR
; Low, JN
; Borges, F
; Gaspar, A
; Mesiti, F
in ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2020, ISSN: 2056-9890, Volume: 76,
Article, Indexed in: crossref, scopus, wos
Abstract
The structure of the title quinoline carboxamide derivative, C26H25N3O, is described. The quinoline moiety is not planar as a result of a slight puckering of the pyridine ring. The secondary amine has a slightly pyramidal geometry, certainly not planar. Both intra- and intermolecular hydrogen bonds are present. Hirshfeld surface analysis and lattice energies were used to investigate the intermolecular interactions.
4.
Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds
Gaspar, A
; Mohabbati, M
; Razzaghi Asl, N
; Miri, R
; Firuzi, O
; Borges, F
in RESEARCH IN PHARMACEUTICAL SCIENCES, 2019, ISSN: 1735-5362, Volume: 14,
Article, Indexed in: authenticus, crossref, scopus, wos
Abstract
Cancer is a major cause of death worldwide and novel anticancer agents for its better management are much needed. Benzopyrone-based compounds, such as chromones, possess several distinctive chemical and biological properties, of which the cytotoxicity against cancer cells seems to be prominent. In this study, two series of compounds based on chromen-4-one (3-10) and chromane-2,4-dione (11-18) scaffolds were synthesized in moderate/high yields and evaluated for cytotoxicity against HL-60, MOLT-4, and MCF-7 cancer cells using MTT assay. In general, the compounds exhibited moderate cytotoxic effects against the cancer cell lines, among which, a superior potency could be observed against MOLT-4 cells. Chroman-2,4dione (11-18) derivatives had overall higher potencies compared to their chromen-4-one (3-10) counterparts. Compound 13 displayed the lowest IC50 values against HL-60 (IC50, 42.0 +/- 2.7 mu M) and MOLT-4 cell lines (IC50, 24.4 +/- 2.6 mu M), while derivative 11 showed the highest activity against MCF-7 cells (IC50, 68.4 +/- 3.9 04). In conclusion, this study provides important information on the cytotoxic effects of chromone derivatives. Benzochroman-2,4-dione has been identified as a promising scaffold, which its potency can be modulated by tailored synthesis with the aim of finding novel and dissimilar anticancer compounds.
5.
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.
6.
Structural elucidation of a series of benzamide derivatives
Oliveira, C
; Gaspar, A
; Gomes, LR
; Low, JN
; Borges, F
in MAGNETIC RESONANCE IN CHEMISTRY, 2018, ISSN: 0749-1581, Volume: 56,
Article, Indexed in: crossref, scopus, wos
7.
Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors (vol 59, pg 5879, 2016)
Reis, J
; Chavarria, D
; Silva, T
; Fernandes, C
; Gaspar, A
; Uriarte, E
; Remiao, F
; Alcaro, S
; Ortuso, F
; Borges, F
in JOURNAL OF MEDICINAL CHEMISTRY, 2018, ISSN: 0022-2623, Volume: 61,
Correction, 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 γ-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. © 2016 American Chemical Society.
8.
Furvina inhibits the 3-oxo-C12-HSL-based quorum sensing system of Pseudomonas aeruginosa and QS-dependent phenotypes
Borges, A
; Sousa, P
; Gaspar, A
; Vilar, S
; Borges, F
; Simoes, M
in BIOFOULING, 2017, ISSN: 0892-7014, Volume: 33,
Article, Indexed in: crossref, scopus, wos
Abstract
Disruption of cell-cell communication or quorum sensing (QS) is considered a stimulating approach for reducing bacterial pathogenicity and resistance. Although several QS inhibitors (QSIs) have been discovered so far their clinical use remains distant. This problem can be circumvented by searching for QSI among drugs already approved for the treatment of different diseases. In this context, antibiotics have earned special attention. Whereas at high concentrations antibiotics exert a killing effect, at lower concentrations they may act as signaling molecules and as such can modulate gene expression. In this study, the antibiotic furvina was shown to be able to cause inhibition of the 3-oxo-C12-HSL-dependent QS system of Pseudomonas aeruginosa. Furvina interacts with the LasI/LasR system. The data were validated by modeling studies. Furvina can also reduce biofilm formation and decrease the production of QS-controlled virulence factors.
9.
Structural elucidation of a series of 6-methyl-3-carboxamidocoumarins
Fonseca, A
; Gaspar, A
; Matos, MJ
; Gomes, LR
; Low, JN
; Uriarte, E
; Borges, F
in MAGNETIC RESONANCE IN CHEMISTRY, 2017, ISSN: 0749-1581, Volume: 55,
Editorial Material, Indexed in: crossref, scopus, wos
10.
Structure of 7-hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one
Low, JN
; Gomes, LR
; Gaspar, A
; Rorges, F
in ACTA CRYSTALLOGRAPHICA SECTION E-CRYSTALLOGRAPHIC COMMUNICATIONS, 2017, ISSN: 2056-9890, Volume: 73,
Article, Indexed in: crossref, scopus, wos
Abstract
Herein, the synthesis and crystal structure of 7-hydroxy-3-(2-methoxyphenyl)-2trifluoromethyl-4H-chromen-4-one, C17H11F3O4, are reported. This isoflavone is used as a starting material in the preparation an array of potent and competitive FPR antagonists. The pyran ring significantly deviates from planarity and the dihedral angle between the benzopyran mean plane and that of the exocyclic benzene ring is 88.18 (4)degrees.In the crystal, O-H center dot center dot center dot O hydrogen bonds connect the molecules into C(8) chains propagating in the [010] direction.