Nineteen previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAO-A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (2b, 2c, 3c, 5b, and 5c), namely those bearing the less bulky alkyls in the Mannich base 8-CH₂NR₂ (R = Me, Et) and the halogens (Cl, Br) at C6 of the 4-coumarin-3-yl moiety, showed moderate inhibitory potencies toward human MAO-A in the single-digit micromolar range (IC₅₀s from 1.49 to 3.04 µM). In particular, the 6′-Cl derivatives 2b and 5b proved to be reversible competitive inhibitors of human MAO-A with K_i values of 0.272 and 0.326 µM. Among the tested compounds, 3c proved to also be a moderate inhibitor of human AChE (IC₅₀ 4.27 µM). Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites consistent enough with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor 3c, full compliance with Lipinski’s rule of five, high probability of gastrointestinal absorption, but low blood–brain barrier (BBB) permeability. While further efforts are required to improve their CNS distribution, herein new phenolic Mannich bases have been identified that may have potential for treating neurodegenerative syndromes.

Background/Objectives: People affected by COVID-19 are exposed to abnormal clotting and endothelial dysfunction, which may trigger thromboembolic events. This study aimed at retrospectively investigating whether oral anticoagulant therapy (OAT), encompassing either direct oral anticoagulants (DOACs), mainly apixaban, or the vitamin K antagonist (VKA) warfarin, could have impacted medium-term mortality in a cohort of SARS-CoV-2 patients. Methods: Among 1238 COVID-19 patients, hospitalized from 17 March 2020 to 15 June 2021, 247 survivors and 247 deceased within 90 days from hospitalization were matched 1:1 based on age, sex, and intensive care unit (ICU) admission within three days. Conditional logistic regression was used to estimate associations by means of odds ratio (OR) with a 95% confidence interval (CI). Results: A univariate regression analysis suggested that OAT, no differently from subcutaneous low-molecular-weight heparins (LMWHs) during hospitalization, has no significant impact (p value > 0.05) on medium-term mortality. A multivariate analysis, limited to baseline variables (i.e., comorbidities and pharmacotherapies at hospital admission) showing significant association (p < 0.05) to mortality in a univariate analysis, revealed that, compared to patients living at 90 days from hospitalization, deceased patients had cancer histories (OR 1.75, CI 1.06–2.90, p = 0.029) or suffered from asthma (OR 2.25, CI 1.13–4.47, p = 0.021). In contrast, heart failure (HF), atrial fibrillation (AF), arteriopathy, chronic obstructive pulmonary disease (COPD), and kidney failure (KF), which, in a univariate analysis, were found to be associated with the endpoint (p < 0.05), lost significance in a multivariate analysis. Therapy at admission with aldosterone antagonists also appeared to be associated with medium-term mortality (OR 2.49, CI 1.52–4.08, p < 0.001); whereas, vitamin D supplementation during hospitalization appeared to be beneficial. Although not conclusive, a search into the Eudravigilance database, combined with consulting a digital predictive platform (PLATO, polypharmacology platform prediction), suggested potential off-target activities, which might contribute to increasing the severity of SARS-CoV-2 infection. Conclusions: This retrospective clinical study furnished evidences of the impact of OAT, comorbidities and other pharmacological treatments on COVID-19 clinical course.

People affected by COVID-19 are exposed to abnormal clotting and endothelial dysfunction which may trigger thromboembolic events. This study aimed at retrospectively investigating whether the oral anticoagulant therapy (OAT), encompassing either direct oral anticoagulants (DOACs), mainly apixaban, or the vitamin K antagonist (VKA) warfarin, may impact on the medium-term mortality in a large cohort of SARS-CoV-2 patients. Among 1238 COVID-19 patients, hospitalized from March 17, 2020, to June 15, 2021, 247 survivors and 247 deceased within 90 days from hospitalization were matched 1:1 based on age, sex and Intensive Care Unit (ICU) admission within three days. Conditional logistic regression was used to estimate associations by means of Odds Ratio (OR) with 95% confidence interval. Compared to patients living at 90 days, those who suffer a fatal event achieved more frequently heart failure, HF (10.5% vs 23.1%; p < 0.001), atrial fibrillation, AF (13.4% vs 22.3%; p = 0.009), as well as respiratory disease or chronic obstructive pulmonary disease (COPD), and renal failure. While HF and AF emerged as the comorbidities mainly associated to medium-term mortality of COVID-19, patients in OAT, no differently from those treated with subcutaneous low-molecular weight heparins (LMWHs) during hospitalization, did not show any significant impact on mortality. In contrast, quite surprisingly, the use of canrenone as mineralcorticoid receptor antagonist in antihypertensive therapy, appeared to worsen the clinical course of COVID-19 patients, whereas vitamin D supplementation showed beneficial effects. The use of a digital predictive platform (PLATO, Polypharmacology pLATform predictiOn) and search into the Eudravigilance database suggested potential associated off-target drug activities, such as modulation of A3 adenosine receptor, and to postulate how aldosterone antagonists might contribute to increase severity of SARS-CoV-2 infection.

About twenty previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAOs A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (2b, 2c, 3c, 5b and 5c), namely those bearing the less bulky alkyls in the Mannich base 8-CH2NR2 (R = Me, Et) and the halogens (Cl, Br) at C6 of the 4-coumarin-3-yl moiety, showed inhibitory potencies towards MAO-A in the single-digit micromolar range (IC50s 1.49÷3.04 µM). Among them, 3c proved to be also the strongest inhibitor of AChE (IC50 = 1.56 µM) in the series. Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites fairly consistent with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor 3c, full compliance with Lipinski’s rule-of-five, high probability of gastrointestinal absorption, and no or poor blood-brain barrier (BBB) permeability. While there is room to improve their CNS distribution, herein we identified 4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-one as a new scaffold of amphoteric MTDLs with potential for neurodegenerative syndromes.