Metal-Free C-H Difluoromethylation of Imidazoles with the Ruppert-Prakash Reagent.

The reaction of trimethyl(trifluoromethyl)silane-tetrabutylammonium difluorotriphenylsilicate (CF3SiMe3-TBAT) with a series of imidazoles gives products of the formal difluorocarbene insertion into the C-H bond at the C-2 position (i.e., C-difluoromethylation). According to NMR spectra, the corresponding 2-(trimethylsilyl)difluoromethyl-substituted derivatives are likely formed as the intermediates in the reaction, and then, they slowly convert to 2-difluoromethyl-substituted imidazoles. Quantum chemical calculations of two plausible reaction mechanisms indicate that it proceeds through the intermediate imidazolide anion stabilized through the interaction with solvent molecules and counterions. In the first proposed mechanism, the anion reacts with difluorocarbene without an activation barrier, and then, the CF2 moiety of the adduct attacks the CF3SiMe3 molecule. After the elimination of the CF3 anion, 2-(trimethylsilyl)difluromethyl-substituted imidazole is formed. Another possible reaction pathway includes silylation of imidazolide anion at the N-3 atom, followed by the barrierless addition of difluorocarbene at the C-2 atom and then by 1,3-shift of the SiMe3 group from N-3 to the carbon atom of the CF2 moiety. Both proposed mechanisms do not include steps with high activation barriers.

Creation of targeted compound libraries based on 3D shape recognition.

In the emerging field of drug discovery, rapid virtual screening methods become extremely valuable, especially when dealing with ultra-large databases of organic small bioactive molecules. In this work, we present a fast, computationally resource-efficient, and simple workflow for screening targeted compound libraries generated from ultra-large virtual chemical space. This workflow aims to find compounds with similar molecular 3D shapes with reference ones, and at the same time to expand chemical diversity and to identify new and potentially active scaffolds. This pipeline ensures the enrichment of the generated libraries with novel chemotypes. Also, it was shown that delicate tailoring of the physicochemical parameters of the search set ensures that all library compounds will possess desired property distributions. A visual inspection has shown that found structures bind to the receptor in the same way as the reference ones. Using our screening workflow, we have created a number of conventional protein-targeted libraries: the GPCRs Targeted Library (531 K compounds) and the Protein Kinases Targeted Library (113 K compounds). The described pipeline and scripts are freely accessible at: https://github.com/ChemSpace-LLC/usrcat_sim .

In Vitro and In Silico Evaluation of Cholinesterase Inhibition by Alkaloids Obtained from Branches of Abuta panurensis Eichler.

Alkaloids are natural products known as ethnobotanicals that have attracted increasing attention due to a wide range of their pharmacological properties. In this study, cholinesterase inhibitors were obtained from branches of Abuta panurensis Eichler (Menispermaceae), an endemic species from the Amazonian rainforest. Five alkaloids were isolated, and their structure was elucidated by a combination of 1D and 2D 1H and 13C NMR spectroscopy, HPLC-MS, and high-resolution MS: Lindoldhamine isomer m/z 569.2674 (1), stepharine m/z 298.1461 (2), palmatine m/z 352.1616 (3), 5-N-methylmaytenine m/z 420.2669 (4) and the N-trans-feruloyltyramine m/z 314.1404 (5). The compounds 1, 3, and 5 were isolated from A. panurensis for the first time. Interaction of the above-mentioned alkaloids with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes was investigated in silico by molecular docking and molecular dynamics. The molecules under investigation were able to bind effectively with the active sites of the AChE and BChE enzymes. The compounds 1-4 demonstrated in vitro an inhibitory effect on acetylcholinesterase with IC50 values in the range of 19.55 µM to 61.24 µM. The data obtained in silico corroborate the results of AChE enzyme inhibition.

Stable Carbenes as Structural Components of Partially Saturated Sulfur-Containing Heterocycles.

Recently, an unusual elongation of the C-S bond was observed experimentally for some sulfur-containing heterocycles. Using a superior ab initio (SCS-MP2/cc-pVTZ) level of theory, we showed that the phenomenon can be explained by a contribution of a donor-acceptor adduct of a carbene with an unsaturated ligand. One may achieve further elongation of the C-S bond, eventually turning it to a coordinate one, by increasing the stability of each part of the system as, e.g., in the utmost case of spiro adducts with Arduengo carbenes. The effect of carbene stability was quantified by employing the isodesmic reactions of carbene exchange.

One-pot parallel synthesis of 1,3,5-trisubstituted 1,2,4-triazoles.

An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible ("REAL") compounds may be generated based on the proposed methodology. Analysis of physicochemical parameters shows that the library contains significant fractions of both drug-like and "beyond-rule-of-five" members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp3-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.

Latent Nucleophilic Carbenes.

Using DFT and ab initio calculations, we demonstrate that noncyclic formamidines can undergo thermal rearrangement into their isomeric aminocarbenes under rather mild conditions. We synthesized the silylformamidine, for which the lowest activation energy in this process was predicted. Experimental studies proved it to serve as a very reactive nucleophilic carbene. The reactions with acetylenes, benzenes, and trifluoromethane proceeded via insertion into sp, sp2, and sp3 CH bonds. The carbene also reacted with the functional groups, such as CHO, COR, and CN at double or triple bonds, displaying high mobility of the trimethylsilyl group. The obtained silylformamidine can be considered as a latent nucleophilic carbene. It can be prepared in bulk quantities, stored, and used when the need arises. Calculation results predict similar behavior for some other silylated formamidines and related compounds.

Antileukemic Activity and Molecular Docking Study of a Polyphenolic Extract from Coriander Seeds.

Leukemia is a group of hematological neoplastic disorders linked to high mortality rates worldwide, but increasing resistance has led to the therapeutic failure of conventional chemotherapy. This study aimed to evaluate in vitro the antileukemic activity and potential mechanism of action of a polyphenolic extract obtained from the seeds of Coriandrum sativum L. (CSP). A methylthiazoletetrazolium assay was performed to assess the CSP cytotoxicity on chronic (K562) and acute (HL60) myeloid leukemia cell lines and on normal Vero cell line. CSP toxicity was also evaluated in vivo using the OECD 423 acute toxicity model on Swiss albino mice. The results demonstrated a remarkable antitumoral activity against K562 and HL60 cell lines (IC50 = 16.86 µM and 11.75 µM, respectively) although no cytotoxicity was observed for the Vero cells or mice. A silico study was performed on the following receptors that are highly implicated in the development of leukemia: ABL kinase, ABL1, BCL2, and FLT3. The molecular docking demonstrated a high affinity interaction between the principal CSP components and the receptors. Our findings demonstrated that CSP extract has remarkable antileukemic activity, which is mainly mediated by the flavonoids, catechins, and rutin, all of which showed the highest binding affinity for the targeted receptors. This study revealed a promising active compound alternative research-oriented biopharmacists to explore.

New 2,3-Benzodiazepine Derivative: Synthesis, Activity on Central Nervous System, and Toxicity Study in Mice.

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light-dark box, and novel object recognition tests under oral administration for acute and sub-acute treatment. We tested the VBZ102 toxicity in mice through a determination of LD50 values and examination of the biochemical and histopathological parameters. The VBZ102 induced an anxiolytic effect at different doses both in the light-dark box and open field tests. Unlike other benzodiazepines (e.g., bromazepam), a sedative effect was noted only after administration of the VBZ102 at 10.0 mg/kg.

In-Vivo Antidiabetic Activity and In-Silico Mode of Action of LC/MS-MS Identified Flavonoids in Oleaster Leaves.

BACKGROUND: Olea europea L. subsp. europaea var. sylvestris (Mill) Lehr (Oleaster) is a wild endemic olive tree indigenous to the Mediterranean region. Olea europea leaves represent a natural reservoir of bioactive molecules that can be used for therapeutic purposes. AIM OF THE STUDY: This work was conducted to study antidiabetic and antihyperglycemic activities of flavonoids from oleaster leaves using alloxan-induced diabetic mice. The mode of action of flavonoids against eight receptors that have a high impact on diabetes management and complication was also investigated using molecular docking. RESULTS: During 28 days of mice treatment with doses 25 and 50 mg/kg b.w, the studied flavonoids managed a severe diabetic state (<450 mg/dL), exhibiting a spectacular antidiabetic and antihyperglycemic activity, and improved mice health status compared to diabetic control. The in-silico mode of action of oleaster flavonoids revealed the inhibition of protein tyrosine phosphatase 1B (PTP1B), Dipeptidyl-peptidase 4 (DPP4), α-Amylase (AAM), α-Glucosidase inhibition, Aldose reductase (AldR), Glycogen phosphorylase (GP), and the activation of free fatty acid receptor 1 (FFAR1). CONCLUSION: The findings obtained in the present work indicate that the flavonoids from the oleaster may constitute a safe multi-target remedy to treat diabetes.

Alkaloids of Abuta panurensis Eichler: In silico and in vitro study of acetylcholinesterase inhibition, cytotoxic and immunomodulatory activities.

Natural products obtained from species of the genus Abuta (Menispermaceae) are known as ethnobotanicals that are attracting increasing attention due to a wide range of their pharmacological properties. In this study, the alkaloids stepharine and 5-N-methylmaytenine were first isolated from branches of Abuta panurensis Eichler, an endemic species from the Amazonian rainforest. Structure of the compounds was elucidated by a combination of 1D and 2D NMR spectroscopic and MS and HRMS spectrometric techniques. Interaction of the above-mentioned alkaloids with acetylcholinesterase enzyme and interleukins IL-6 and IL-8 was investigated in silico by molecular docking. The molecules under investigation were able to bind effectively with the active sites of the AChE enzyme, IL-6, and IL-8 showing affinity towards the proteins. Along with the theoretical study, acetylcholinesterase enzyme inhibition, cytotoxic, and immunomodulatory activity of the compounds were assessed by in vitro assays. The data obtained in silico corroborate the results of AChE enzyme inhibition, the IC50 values of 61.24µM for stepharine and 19.55µM for 5-N-methylmaytenine were found. The compounds showed cytotoxic activity against two tumor cell lines (K562 and U937) with IC50 values ranging from 11.77 µM to 28.48 µM. The in vitro assays revealed that both alkaloids were non-toxic to Vero and human PBMC cells. As for the immunomodulatory activity, both compounds inhibited the production of IL-6 at similar levels. Stepharine inhibited considerably the production of IL-8 in comparison to 5-N-methylmaytenine, which showed a dose dependent action (inhibitory at the IC50 dose, and stimulatory at the twofold IC50 one). Such a behavior may possibly be explained by different binding modes of the alkaloids to the interleukin structural fragments. Occurrence of the polyamine alkaloid 5-N-methylmaytenine was reported for the first time for the Menispermaceae family, as well as the presence of stepharine in A. panurensis.

Synthesis, molecular docking studies, and larvicidal activity evaluation of new fluorinated neonicotinoids against Anopheles darlingi larvae.

Anopheles darlingi is the main vector of malaria in Brazil, characterized by a high level of anthropophilia and endophagy. Imidacloprid, thiacloprid, and acetamiprid are the most widespread insecticides of the neonicotinoid group. However, they produce adverse effects on the non-target insects. Flupyradifurone has been marketed as an alternative to non-fluorinated neonicotinoids. Neonicotinoids containing trifluoroacethyl substituent reveal increased insecticidal activity due to higher hydrophobicity and metabolic stability. We synthesized novel neonicotinoid insecticides containing fluorinated acceptor groups and their interactions were estimated with the nicotinic acetylcholine receptor (nAChR) binding site by molecular docking studies, to evaluate their larvicidal activity against A. darlingi, and to assess their outdoor photodegradation behavior. New neonicotinoid analogues were prepared and characterized by NMR and mass-spectrometry. The synthesized molecules were modelled by time-dependent density functional theory and analyzed, their interaction with nAChR was investigated by molecular docking. Their insecticide activity was tested on Anopheles larvae collected in suburban area of Manaus, Brazil. Four new fluorinated neonicotinoid analogs were prepared and tested against 3rd instars larvae of A. darlingi showing high larvicidal activity. Docking studies reveal binding modes of the synthesized compounds and suggest that their insecticidal potency is governed by specific interactions with the receptor binding site and enhanced lipophilicity. 2-Chloro-5-(2-trifluoromethyl-pyrrolidin-1-ylmethyl)pyridine 5 showed fast degradation in water maintaining high larvicidal activity. All obtained substances possessed high larvicidal activity in low concentrations in 48 hours of exposure, compared to commercial flupyradifurone. Such activity is connected to a unique binding pattern of the synthesized compounds to insect's nAChR and to their enhanced bioavailability owing to introduction of fluorinated amino-moieties. Therefore, the compounds in question have a high potential for application as control agents for insects transmitting tropical diseases, and they will be less persistent in the environment.