COVID-19 therapy: What weapons do we bring into battle?

Urgent treatments, in any modality, to fight SARS-CoV-2 infections are desired by society in general, by health professionals, by Estate-leaders and, mainly, by the scientific community, because one thing is certain amidst the numerous uncertainties regarding COVID-19: knowledge is the means to discover or to produce an effective treatment against this global disease. Scientists from several areas in the world are still committed to this mission, as shown by the accelerated scientific production in the first half of 2020 with over 25,000 published articles related to the new coronavirus. Three great lines of publications related to COVID-19 were identified for building this article: The first refers to knowledge production concerning the virus and pathophysiology of COVID-19; the second regards efforts to produce vaccines against SARS-CoV-2 at a speed without precedent in the history of science; the third comprehends the attempts to find a marketed drug that can be used to treat COVID-19 by drug repurposing. In this review, the drugs that have been repurposed so far are grouped according to their chemical class. Their structures will be presented to provide better understanding of their structural similarities and possible correlations with mechanisms of actions. This can help identifying anti-SARS-CoV-2 promising therapeutic agents.

Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.

Topoisomerase inhibition and albumin interaction studies of acridine-thiosemicarbazone derivatives.

In the present study, acridine-thiosemicarbazones (ATD) derivatives were tested for their interaction properties with BSA through UV-Vis absorption and fluorescence spectroscopic studies. Both hyperchromic and hypochromic effects, as well as red or blue shifts were demonstrated after the derivatives were added to the BSA. Values for the binding constant (Kb) ranged from 1.62 × 104 to 8.71 × 105 M-1 and quenching constant (KSV) from 3.46 × 102 to 7.83 × 103 M-1 indicating a good affinity to BSA protein. Complementary, two compounds were selected to assess their inhibition activity against topoisomerase IIα enzyme, of which derivative 3a presented the best result. Moreover, to evaluate protein-ligand interactions, as well as the antitopoisomerase potential of these compounds, tests of molecular modeling were performed between all compounds using the albumin and Topoisomerase IIα/DNA complex. Finally, in silico studies showed that all derivatives used in this research displayed good oral bioavailability potential.

Synthesis, DNA and protein interactions and human topoisomerase inhibition of novel Spiroacridine derivatives.

Nine new spiroacridine derivatives were synthetized by introducing cyano-N-acylhydrazone group between the acridine and phenyl-substituted rings followed by spontaneous cyclization. The new compounds were assayed for their DNA binding properties, human topoisomerase IIα inhibition and bovine serum albumin (BSA) interaction. Besides, docking analysis were performed in order to better understanding the biomolecule-compounds interactions. All compounds interacted with BSA which was demonstrated by the fluorescence suppression constant of 104 M-1. Compounds with chloro and NO2 substituents at that para-position on phenyl ring demonstrated the best results for BSA interaction. DNA binding constant determined by UV-vis data demonstrated high values for AMTAC-11 and AMTAC-14, 1.1 × 108 M-1 and 4.8 × 106 M-1, respectively, and all others presented constant values of 105 M-1. AMTAC-06 with chloro at para-position on phenyl ring presented a topoisomerase II inhibition of 84.34% in comparison to the positive controls used. Docking studies indicated that AMTAC-06 is able to intercalate the DNA base pairs at topoisomerase IIα active site, preventing DNA connection after break, in a process known as poisoning. Topoisomerase enzyme inhibition result was correlated to BSA interaction profile, since AMTAC-06 showed the best results in both analysis. The findings obtained here proved that methoxy or chloro substitution on phenyl ring at para-position is fundamental for in vitro activity of new spiroacridine derivatives, and indicates that AMTAC-06 is a promising entity and should serve as a lead compound in the development of new DNA and protein binders, as well as human topoisomerase II inhibitors.

DNA binding and Topoisomerase inhibition: How can these mechanisms be explored to design more specific anticancer agents?

DNA is considered one of the most promising targets of molecules with anticancer activity potential. Its key role in various cell division mechanisms, which commands the intense multiplication of tumor cells, is considered in studies with compounds whose mechanisms of action suggest likeliness of interaction. In addition, inhibition of enzymes that actively participate in biological functions of cells such as Topoisomerase, is seen as a primary factor for conducting several events that result in cell death. Discovery of new anticancer chemotherapeutical capable of interacting with DNA and inhibiting Topoisomerase enzymes is highlighted in anticancer research. The present review aims at showing through distinct biological tests the performance of different candidates to anticancer drugs and their respective chemical modifications, which are crucial and/or determinant for DNA affinity and inhibition of important enzymes in cells' vital processe to either separately or synergistically optimize anticancer activity.

Synthesis of thiophene-thiosemicarbazone derivatives and evaluation of their in vitro and in vivo antitumor activities.

A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 µM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 µM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.