Natural products (NPs), being evolutionary selected over millions of years to bind to biological macromolecules, remain an important source of inspiration for medicinal chemists even after the advent of efficient drug discovery technologies such as combinatorial chemistry and high-throughput screening. Thus, there is a strong demand for efficient and user-friendly computational tools that allow to analyze large libraries of NPs. In this context, we present NP Navigator – a free, intuitive online tool for visualization and navigation through the chemical space of NPs and NP-like molecules^[1] (https://infochm.chimie.unistra.fr/npnav/chematlas_userspace ). It is based on the hierarchical ensemble of more than 200 Generative Topographic Maps(GTM)^[2], featuring NPs from the COlleCtion of Open NatUral producTs (COCONUT), bioactive compounds from ChEMBL and commercially available molecules from ZINC. NP Navigator allows to efficiently analyze different aspects of NPs - chemotype distribution, physicochemical properties, reported and/or predicted biological activity and commercial availability of NPs. Users are welcome not only to browse through hundreds of thousands of compounds from ZINC, ChEMBL and COCONUT but also project a several external molecules that play the role of “chemical trackers” allowing to trace particular chemotypes in the NP chemical space and detect analogs of the compound of interest.

[1] Y. Zabolotna, P. Ertl, D. Horvath, F. Bonachera, G. Marcou, A. Varnek, NP Navigator: a New Look at the Natural Product Chemical Space, 2021.
[2] C. M. Bishop, M. Svensén, C. K. I. Williams, Neural Comput. 1998, 10, 215-234.

Linearolactone (LL) isolated from Salvia polystachya presents antiparasitic activity against E. histolytica and G. lamblia through ROS production, an apoptosis-like process, and alteration of the actin cytoskeleton. However, the possible toxicological effects or molecular mechanisms of LL are still not understood. The aim of this study was to determine the pharmacological and toxicological properties of LL by bioinformatic analyzes. The pharmacological activities, toxicological risks, and molecular targets of LL were determinate by free software such as Molsoft©, Molinspiration©, ToxiM©, SuperCYPsPred©, and SEA©. Molecular docking with key proteins for the pathogenic activity of Entamoeba histolytica trophozoites, such as myosin-II and calreticulin, was performed with AutoDock-Vina and UCSF-Chimera. Results revealed that LL present drug-likeness of -0.55 and ToxiM of 0.958 due to medium toxicity associated with interactions in nuclear receptors (0.66), GPCR ligands (0.65), and enzymatic inhibitions (0.47) related to the cytochrome-P450 system (CYP3A4, low). Results indicate that LL is a hydrophobic molecule (LogP: 1.59) with intermediate intestinal absorption (TPSA: 65.75, CACO-2 permeability) and medium blood-brain barrier penetration (3.86). SEA analysis demonstrated that the potential target pharmacophores are OPRK1 (P-Value: 6.49 x10-37, Max TC: 0.49) and Nlrp3 (P-Value: 3.90 x10-19, Max TC: 0.36) in humans. Molecular docking of LL with E. histolytica proteins showed high affinity to ATP-binding catalytic site in heavy-chain (GLU-187.A, THR-186.A, ASN-234.B) of myosin-II (-8.30 Kcal/mol), as well as in the chain-A and C (LYS-199.A, LYS-152.C) of calreticulin (-8.77 Kcal/mol). As conclusions, LL is a compound with possible moderate toxicity, sedative effects on CNS, and anti-inflammatory properties. In addition, LL probably inhibits amoebic liver abscess formation through interactions with myosin-II and calreticulin from E. histolytica, but in-depth studies are necessary to confirm these claims.

Chronic wounds (CW) create numerous entry ways for pathogen invasion and prosperity, further damaging host tissue and hindering tissue remodelling and repair. Essential oils (EOs) exert quick and efficient antimicrobial (AM) action, unlikely to induce bacterial resistance. Cinnamon leaf and clove oils (CLO and CO) exert strong AM activity, namely against Staphylococcus aureus and Pseudomonas aeruginosa. Chitosan (CS) is a natural and biodegradable cationic polysaccharide, also widely known for its AM features. CS and poly (vinyl alcohol) (PVA) films were prepared (ratio 30/70; 9%wt) by solvent casting and phase inversion method. Film’s thermal stability and chemical composition data reinforced polymer blending and EO entrapment. Films were supplemented with 1 and 10wt% of EO in relation to total polymeric mass. Film’s thickness and degree of swelling (DS) tended to increase with EO loading amount, particularly with 10wt% CLO (*p<0.05). AM testing (agar diffusion assay and time-kill kinetics) revealed that CS films alone were effective against both bacteria, and capable of eradicating all P. aeruginosa within the hour (***p<0.001). Still, loaded CS/PVA films showed significantly improved AM traits in relation to unloaded films right after 2h of contact. This study is a first proof of concept that CLO and CO can be dispersed into CS/PVA films and show bactericidal effects, particularly against S. aureus, this way paving the way for efficient CW therapeutics.

The devastating nature of the SARS-CoV-2 pandemic has fostered the need for potent therapeutics to manage or curb its severity. As a response, several studies on drug repurposing, vaccine design and optimizing natural phytochemicals are ongoing. This study aims at screening for potent and novel anti-COVID phytochemicals from the rhizome of Curcuma longa. A phytochemical library of 50 non-ubiquitous bioactive compounds from the rhizome of Curcuma longa was retrieved from Dr. Duke's phytochemical and ethnobotanical database (https://phytochem.nal.usda.gov/phytochem/search). The compounds in the library were docked against the receptor binding domain (RBD) of SARS-CoV-2 (PDB ID: 7EAM_1). Three compounds - Quercetin; 1,7-Bis-(4-hydroxyphenyl)-1-heptene-3,5-dione; and Cyclocurcumin, were selected based on their higher docking score than the standard repurposed drug (Arbidol). This study further examined the interactions of the novel 1,7-Bis-(4-hydroxyphenyl)-1-heptene-3,5-dione (BHHD) in the binding pocket as well as its ADMET properties. Excellent interaction was observed between the atoms of BHHD and amino acid residues known to foster the viral entry into the host. Furthermore, the ADMET result for BHHD was impressive for a lead molecule. Therefore, this study recommends for further investigation on the potency and toxicity of BHHD both on cell lines and animal models.

Monoterpenes, which have a unique diverse structure and are inexpensive, available and often enantiomerically pure, are an attractive renewable raw material for the development of physiologically active agents. One of the important methods to the utilization of monoterpenes is their interaction with carbonyl compounds resulting in heterocyclic compounds. Often these products exhibit analgesic, antiviral or neuroprotective properties. Earlier, we discovered anti-influenza A (H1N1) virus activity of several compounds with a hydro-2H-chromene scaffold, which were synthesized by the Prins reaction using p-menthane alcohols and carbonyl compounds; montmorillonite K10 or nanosized halloysite catalyst were used as the reaction catalysts [1]. Chromenols produced from an (–)-isopulegol and aliphatic ketones (acetone and cyclopentanone) demonstrated high activity in combination with low toxicity against the influenza virus [1].

The introduction of the fluorine atom into the molecule is an important strategy in the development of new biologically active compounds, which enables changing lipophilicity and electrostatic interactions and increasing the metabolic stability of compounds and, so affects their physiological activity. Here we synthesized fluoro- and hydroxy-containing octahydro-2H-chromenes by the Prins reaction starting from an (–)-isopulegol and a wide range of aromatic aldehydes in the presence of the BF₃∙Et₂O/H₂O system acting as both an acid catalyst and a fluorine source. Activity of the synthesized compounds against the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. The highest activity was demonstrated by fluoro- and hydroxy-containing 2,4,6-trimethoxybenzaldehyde derivatives. These compounds were supposed to be capable of binding to viral hemagglutinin, which is an agreement with data on the effect of compounds on the viral fusogenic activity as well as with molecular docking studies.

[1] N.Salakhutdinov, K.Volcho, O.Yarovaya, Pure Appl. Chem., 2017;89:1105-1117.