Synthesis and evaluation of thymol-based synthetic derivatives as dual-action inhibitors against different strains of h. pylori and AGS cell line

Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and 1H/13C/19F NMR spectra. The analysis of structure-activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis

An updated patent review on monoamine oxidase (MAO) inhibitors

Introduction: Monoamine oxidase (MAO) inhibitors are currently used as antidepressants (selective MAO-A inhibitors) or as co-adjuvants for neurodegenerative diseases (selective MAO-B inhibitors). The research within this field is attracting attention due to their crucial role in the modulation of brain functions, mood, and cognitive activity, and monoamine catabolism. Areas covered: MAO inhibitors (2018–2021) are discussed according to their chemotypes. Structure–activity relationships are derived for each chemical scaffold (propargylamines, chalcones, indoles, benzimidazoles, (iso)coumarins, (iso)benzofurans, xanthones, and tetralones), while the chemical entities were divided into newly synthesized molecules and natural metabolites. The mechanism of action and type of inhibition are also considered. Lastly, new therapeutic applications are reported, which demonstrates the clinical potential of these inhibitors as well as the possibility of repurposing existing drugs for a variety of diseases. Expert opinion: MAO inhibitors here reported exhibit different potencies and isoform selectivity. These compounds are clinically licensed for multi-faceted neurodegenerative pathologies due to their ability to also act against other relevant targets (cholinesterases, inflammation, and oxidative stress). Moreover, the drug repurposing approach is an attractive strategy by which MAO inhibitors may be applied for the treatment of prostate cancer, inflammation, vertigo, and type 1 diabetes

Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors

The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs. In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform. In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies

Peptidyl 3-Substituted 1-Hydroxyureas as Isosteric Analogues of Succinylhydroxamate MMP Inhibitors

To evaluate N-hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N-hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H-d-Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4-5 orders of magnitude) than the isosteric (R)-succinylhydroxamate analogue, which displays IC(50) in the range of nM vs MMP-1, -3, -7 and sub-nM vs MMP-2, -8, and -9. The peptidyl 1-hydroxyurea 1a attained an IC(50) of 20muM vs MMP-9, and substantially approaches inhibition of known N-hydroxyureas based on aminoacids or peptides against other zinc metalloenzymes and non-peptidic N-hydroxyureas against MMPs. Strong preference of the O-N1-CO unit for the antiperiplanar amide bond conformation seems to be the major limit for more effective zinc chelation. Methylation of a peptidyl 1-hydroxyurea at N3, to promote the synperiplanar O-N1-CO conformation required for zinc chelation and improve affinity, resulted in release of a methylimidazolidine-2,4-dione through an undesired intramolecular reaction reminiscent of the Edman peptide degradation

Biofilm and quorum sensing inhibitors : the road so far

Introduction: Biofilm is a complex aggregation of microorganisms characterized by the presence of a dynamic, adhesive and protective extracellular matrix composed of polysaccharides, proteins and nucleic acids. It is estimated that the vast majority of human infections are related to the biofilm in which the microorganisms reside and communicate with each other (Quorum Sensing), surviving in hostile environmental conditions. Areas covered: This review provides a comprehensive focus on the development state of promising strategies against biofilm production and eradication describing chemical structures, results, administration routes, pharmaceutical compositions, and SARs as well as their shortcomings within the 2019-2020 range. Expert opinion: New pharmacological targets have been explored in the past years, allowing a broader therapeutic arsenal against biofilm-related pathologies. The Quorum Sensing system was targeted as well in order to avoid the development of intrinsically antibiotic-resistant bacteria and to enhance a proper host defense

Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors

To evaluate N-hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N-hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H-D-Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4e5 orders of magnitude) than the isosteric (R)-succinylhydroxamate analogue, which displays IC50 in the range of nM vs MMP-1, -3, -7 and sub-nM vs MMP-2, -8, and -9. The peptidyl 1-hydroxyurea 1a attained an IC50 of 20 mM vs MMP-9, and substantially approaches inhibition of known N-hydroxyureas based on aminoacids or peptides against other zinc metalloenzymes and non-peptidic N-hydroxyureas against MMPs. Strong preference of the OeN1eC]O unit for the antiperiplanar amide bond conformation seems to be the major limit for more effective zinc chelation. Methylation of a peptidyl 1-hydroxyurea at N3, to promote the synperiplanar OeN1eC]O conformation required for zinc chelation and improve affinity, resulted in release of a methylimidazolidine-2,4-dione through an undesired intramolecular reaction reminiscent of the Edman peptide degradation