Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.

In this work we described the synthesis and antimicrobial evaluation of 7-arylamino-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylates derivatives that exhibited remarkable activity against two Gram-negative strains of clinical importance.

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Background: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains. Objective: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains. Method: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays. Result: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. Conclusion: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

Leishmaniasis is a neglected tropical disease caused by protozoan parasites belonging to the genus Leishmania. Currently, the drugs available for treatment of this disease present high toxicity, along with development of parasite resistance. In order to overcome these problems, efforts have been made to search for new and more effective leishmanicidal drugs. The aim of this study was to synthesize and investigate the leishmanicidal effect of N,N′-disubstituted thioureas against Leishmania amazonensis, with evaluation of their in silico pharmacokinetics and toxicity profiles. Our results showed that different thioureas could be obtained in high to moderate yields using simple reaction conditions. Nine thiourea derivatives (3e, 3i, 3k, 3l, 3p, 3q, 3v, 3x and 3z) were active against parasite promastigotes (IC 50 21.48-189.10 µM), with low cytotoxicity on mice peritoneal macrophages (CC 50 >200 µM), except for thiourea 3e (CC 50 =49.22 µM). After that, the most promising thioureas (3k, 3l, 3p, 3q and 3v) showed IC 50 ranging from 70 to 150 µM against L. amazonensis amastigotes in infected macrophages. Except for thiourea 3p, the leishmanicidal activity of the derivatives were independent of nitric oxide (NO) production. Thioureas 3q and 3v affected promastigotes cell cycle without disturbing the mitochondrial membrane potential. Furthermore, our derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. These data indicate that thiourea derivatives are good candidates as leading compounds for the development of new leishmanicidal drugs.

This article reports a novel virtual screening algorithm seeking the rational identification of novel lead anticoagulants. Seven 5-(3-methyl-1-aryl-1H-pyrazol-4-yl)-1H-tetrazoles and seven novel 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazoles were obtained in three steps starting from arylhydrazine hydrochlorides as raw materials in good yields: 50-72% and 50-85%, respectively. All compounds were submitted to an in silico target-base pipeline named integrated multiplex analysis virtual screening (IMA-VS), which comprises the evaluation of their (i) fitting physicochemical properties to the chemical environment of the target enzyme; (ii) active-site homing electrostatic potential to the target enzyme; (iii) structural fitting to the target active site through molecular docking; and (iv) overall absorption, distribution, metabolism, excretion and toxicity (ADMET) profile. After the virtual selection of potential anticoagulant hits, all molecules were synthesized and candidates were evaluated in vitro for their anticoagulant and hemolytic profile. The most promising candidate pointed out by IMA-VS was compound 1-(3',4'-dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazole that shown to display factor Xa (FXa)-specific inhibitory activity in vitro, acting as an uncompetitive inhibitor with an inhibition constant (Ki) = 61.16 ± 12.96 µM, in addition to the lowest hemolytic activity of the series. Further experiments revealed the antithrombotic activity of this compound in an in vivo model of arterial thrombosis induced by FeCl 3 .

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