New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling.

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants. Currently, ribavirin, a nucleoside analog containing a 1,2,4-triazole-3-carboxamide moiety, is a first-line drug for its treatment, however, its clinical use has been limited due to its side effects. Here, we designed two new nitroaryl-1,2,3-triazole triterpene derivatives as novel anti-RSV drugs. Their anti-RSV and cytotoxic activity were evaluated in vitro, RSV protein F gene effects by RT-PCR and molecular modeling with inosine monophosphate dehydrogenase (IMPDH) were performed. Compound 8 was the best performing compound, with an EC50 value of 0.053 µM, a TI of 11160.37 and it inhibited hRSV protein F gene expression by approximately 65%. Molecular docking showed a top-ranked solution located in the same region occupied by crystallographic ligands in their complex with IMPDH. The results obtained in this study suggest that compound 8 might be a new anti-RSV candidate.

Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.

Background: The new coronavirus pandemic has had a significant impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus. Materials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was recently published. Results and conclusion: We identified seven drugs with different original indications that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.

1,2,3-Triazole tethered 2-mercaptobenzimidazole derivatives: design, synthesis and molecular assessment toward C6 glioma cell line.

Aim: Glioblastoma multiforme (GBM) is an aggressive cancer with very limited clinical therapies. Herein, we have designed novel mercaptobenzimidazole derivatives (1-7) as multitarget antineoplastic drugs and assessed their antiproliferative profiles on an experimental model for GBM, the C6 glioma line. Results: The target compounds were synthesized in few steps with reasonable yields (33-90%). Compounds 1 (∼18 µM) and 4 (∼20 µM) showed dose-dependent antiproliferative effects on C6 glioma and significantly increased early apoptosis, but only 4 disrupted the cell cycle progression and did not induce autophagy. Docking simulations suggested these compounds as dual kinase and colchicine binding site inhibitors. Conclusion: In spite of the limited selective toxicity, 4 hold the potential to be further optimized for the treatment of GBM.

In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs.

The in silico evaluation for the three previously synthesized compounds (Methyl (MMA), propyl (PMA) and isopropyl (IMA) N-methylanthranilate), MMA and IMA originally found in the leaf essential oil of Choisya ternata, provided a very good confirmation for the in vivo pharmacological results obtained with such compounds for a number of pharmacological targets. This manuscript dealt with their assessment in six pharmacological targets to understanding anti-inflammatory, antinociceptive, anxiolytic, antidepressant and anti-allergic activities using docking molecular as well as their pharmacokinetics and toxicological parameters prediction. The compound IMA seems to be the best one when all the combined parameters are put together. Interestingly this compound presented the best in vivo profile in previous studies by the group. Derivatives of the three original molecules were proposed. Overall the second modification (5-[2-(methoxycarbonyl)anilino]pentanoic acid, 5-[2-(propoxycarbonyl)anilino]pentanoic acid and 5-(2-{[(propan-2-yl)oxy]carbonyl}anilino)pentanoic acid) of all three original molecules was the one that achieved highest score in molecular docking and a better combination of the other parameters. Further research as in the obtaining of such derivatives via synthesis and their in vivo testing to confirm their higher pharmacological potential is currently on the way.

GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.

Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6ß3ß4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.