Inhibitory effects of 190 compounds against SARS-CoV-2 Mpr o protein: Molecular docking interactions.

COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines. However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (Mpr o ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 Mpro . Twenty-five compounds inhibited Mpro with inhibitory constant values (Ki ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of Mpro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

Chalcone Derivative Induces Flagellar Disruption and Autophagic Phenotype in Phytomonas serpens In Vitro.

Phytomonas serpens is a trypanosomatid phytoparasite, found in a great variety of species, including tomato plants. It is a significant problem for agriculture, causing high economic loss. In order to reduce the vegetal infections, different strategies have been used. The biological activity of molecules obtained from natural sources has been widely investigated to treat trypanosomatids infections. Among these compounds, chalcones have been shown to have anti-parasitic and anti-inflammatory effects, being described as having a remarkable activity on trypanosomatids, especially in Leishmania species. Here, we evaluated the antiprotozoal activity of the chalcone derivative (NaF) on P. serpens promastigotes, while also assessing its mechanism of action. The results showed that treatment with the derivative NaF for 24 h promotes an important reduction in the parasite proliferation (IC50/24 h = 23.6 ± 4.6 µM). At IC50/24 h concentration, the compound induced an increase in reactive oxygen species (ROS) production and a shortening of the unique flagellum of the parasites. Electron microscopy evaluation reinforced the flagellar phenotype in treated promastigotes, and a dilated flagellar pocket was frequently observed. The treatment also promoted a prominent autophagic phenotype. An increased number of autophagosomes were detected, presenting different levels of cargo degradation, endoplasmic reticulum profiles surrounding different cellular structures, and the presence of concentric membranar structures inside the mitochondrion. Chalcone derivatives may present an opportunity to develop a treatment for the P. serpens infection, as they are easy to synthesize and are low in cost. In order to develop a new product, further studies are still necessary.

Synthesis of chalcone derivatives by Claisen-Schmidt condensation and in vitro analyses of their antiprotozoal activities.

Chalcone is a molecule with known biological activities. Based on this, a series of chalcone derivatives bearing methyl, phenyl or furanyl substituents at different positions of A and B rings were synthesised, characterised, and evaluated regarding antiprotozoal activity. Molecules were synthesised via base catalyzed Claisen-Schmidt condensation and characterised by IR and NMR spectral data. Antiprotozoal activity against Phytomonas serpens, Leishmania amazonensis and Acanthamoeba polyphaga was performed. All compounds inhibited more than 50% of the growth of P. serpens while five had this effect on L. amazonensis and all of them no more than 35% of inhibition on A. polyphaga. Remarkably interesting antiprotozoal effects were recorded with compound 5, with IC50 of 1.59 µM for P. serpens and 11.49 µM for L. amazonensis. The addition of a naphthyl group to the B ring can be postulated to be the cause of the 10 times increase observed in its trypanocidal activity.

Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2.

BACKGROUND: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. OBJECTIVE: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. METHODS: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. RESULTS: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. CONCLUSION: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.

Chalcone-based molecules: Experimental and theoretical studies on the two-photon absorption and molecular first hyperpolarizability.

Five chalcone-based molecules denominated by C-3 ((E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one), C-4 ((E)-1,3-bis(4-methoxyphenyl)prop-2-en-1-one), C-5 ((E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)prop-2-en-1-one), C-6 ((E)-3-(naphthalen-1-yl)-1-phenylprop-2-en-1-one) and C-7 ((E)-1-(4-methoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one) were synthesized by Claisen-Schmidt reaction in solution of NaOH in water/ethanol 2:1. The aldehydes used were benzaldehyde, anisaldehyde, and ß-naphthaldehyde, while the used ketones were acetophenone, p-methoxyacetophenone, and 3,4-methylenedioxyacetophenone. Z-scan and hyper-Rayleigh scattering techniques were used to study the nonlinear optical properties of these compounds in dichloromethane medium. By using Z-scan technique with femtosecond pulses, two-photon absorption cross-sections (σTPA) were determined, while the first molecular electronic hyperpolarizabilities (ßHRS) were evaluated by the hyper-Rayleigh scattering technique, with picosecond pulses. From the recorded two-photon absorption spectra, it was identified that compound C-7 presented the highest σTPA, regarding the HOMO-LUMO transition, with a value of 40 GM, while C-6 achieved the lowest value for the same transition with 13 GM. Concerning the values of the first molecular hyperpolarizability, compound C-4 presented the highest value, 38 × 10-30 cm4 statvolt-1, while C-3 presented the lowest ßHRS value of about 16 × 10-30 cm4 statvolt-1. Time-dependent density functional theory calculations were used to simulate the one- and two-photon absorption spectra, as well to predict the theoretical value of ßHRS in dichloromethane and vacuum medium.