Regioselective Claisen-Schmidt Adduct of 2-Undecanone from Houttuynia cordata Thunb as Insecticide/Repellent against Solenopsis invicta and Repositioning Plant Fungicides against Colletotrichum fragariae.

The U.S. Department of Agriculture (USDA) has established research programs to fight the phytopathogen Colletotrichum fragariae and the invasive red imported fire ant, Solenopsis invicta. C. fragariae is known to cause anthracnose disease in fruits and vegetables, while S. invicta is known for its aggressive behavior and painful stings and for being the cause of significant damage to crops, as well as harm to humans and animals. Many plants have been studied for potential activity against C. fragariae and S. invicta. Among the studied plants, Houttuynia cordata Thunb has been shown to contain 2-undecanone, which h is known for its antifungal activity against Colletotrichum gloesporioides. Based on the mean amount of sand removed, 2-undecanone showed significant repellency at 62.5 µg/g, similar to DEET (N,N-diethyl-meta-toluamide), against S. invicta. The 2-Undecanone with an LC50 of 44.59 µg/g showed toxicity against S. invicta workers. However, neither H. cordata extract nor 2-undecanone had shown activity against C. fragariae despite their known activity against C. gloesporioides, which in turn motivates us in repositioning 2-undecanone as a selected candidate for a Claisen-Schmidt condensation that enables access to several analogs (2a-f). Among the prepared analogs, (E)-1-(3-methylbenzo[b]thiophen-2-yl)dodec-1-en-3-one (2b) and (E)-1-(5-bromothiophen-2-yl)dodec-1-en-3-one (2f) showed promising activity against C. fragariae, revealing a distinctive structural activity relationship (SAR). The generated analogs revealed a clear regioselectivity pattern through forming the C=C alkene bond at position C-1. These data open the window for further lead optimization and product development in the context of managing C. fragariae and S. invicta.

Traditional Use, Phytochemical Profiles and Pharmacological Properties of Artemisia Genus from Central Asia.

The flora of Kazakhstan is characterized by its wide variety of different types of medicinal plants, many of which can be used on an industrial scale. The Traditional Kazakh Medicine (TKM) was developed during centuries based on the six elements of ancient Kazakh theory, associating different fields such as pharmacology, anatomy, pathology, immunology and food nursing as well as disease prevention. The endemic Artemisia L. species are potential sources of unique and new natural products and new chemical structures, displaying diverse bioactivities and leading to the development of safe and effective phytomedicines against prevailing diseases in Kazakhstan and the Central Asia region. This review provides an overview of Artemisia species from Central Asia, particularly traditional uses in folk medicine and the recent numerous phytochemical and pharmacological studies. The review is done by the methods of literature searches in well-known scientific websites (Scifinder and Pubmed) and data collection in university libraries. Furthermore, our aim is to search for promising and potentially active Artemisia species candidates, encouraging us to analyze Protein Tyrosine Phosphatase 1B (PTP1B), α-glucosidase and bacterial neuraminidase (BNA) inhibition as well as the antioxidant potentials of Artemisia plant extracts, in which endemic species have not been explored for their secondary metabolites and biological activities so far. The main result of the study was that, for the first time, the species Artemisia scopiformis Ledeb. Artemisia albicerata Krasch., Artemisia transiliensis Poljakov, Artemisia schrenkiana Ledeb., Artemisia nitrosa Weber and Artemisia albida Willd. ex Ledeb. due to their special metabolites, showed a high potential for α-glucosidase, PTP1B and BNA inhibition, which is associated with diabetes, obesity and bacterial infections. In addition, we revealed that the methanol extracts of Artemisia were a potent source of polyphenolic compounds. The total polyphenolic contents of Artemisia extracts were correlated with antioxidant potential and varied according to plant origin, the solvent of extraction and the analytical method used. Consequently, oxidative stress caused by reactive oxygen species (ROS) may be managed by the dietary intake of current Artemisia species. The antioxidant potentials of the species A. schrenkiana, A. scopaeformis, A. transiliensis and Artemisia scoparia Waldst. & Kitam. were also promising. In conclusion, the examination of details between different Artemisia species in our research has shown that plant materials are good as an antioxidant and eznyme inhibitory functional natural source.

Identification of an Orally Bioavailable, Brain-Penetrant Compound with Selectivity for the Cannabinoid Type 2 Receptor.

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 µM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.

First In Class (S,E)-11-[2-(Arylmethylene)Hydrazono]-PBD Analogs As Selective CB2 Modulators Targeting Neurodegenerative Disorders.

Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction towards CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy towards the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed K i of 0.49 and 4.7 µM towards CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1.

Challenges and future directions of potential natural products leads against 2019-nCoV outbreak.

Except for Remdesivir® no other drug or vaccine has yet been approved to treat the coronavirus disease (COVID-19) caused by the virus known as, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir® an small molecule and nucleic acid analogue, it is used to treat adults and children with laboratory confirmed COVID-19, only administrated in hospital settings. Small molecules and particularly natural products count for almost fifty percent of the commercially available drugs, several of them are marketed antiviral agents and those can be a potential agent to treat COVID-19 infections. This short review rationalized different key natural products with known activity against coronaviruses as potential leads against COVID-19.

2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study.

Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies.