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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 toward 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 toward the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed Ki of 0.49 and 4.7 μM toward 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.

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.

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.

This paper presents the results of investigations on conformation peculiarities of the condensation products of piperidine-4-ones containing arylidene, hydroxyarylmethyl as well as both arylidene and hydroxyarylmethyl substituents. Synthesized α, β-unsaturated ketones can be used to investigate conformation of cycles fixing a conjugated system of carbonyl and double bonds. Synthesis of α, β-unsaturated piperidine-4-ones was carried out according to the reaction of Claisen-Schmidt by condensation of piperidine-4-ones with aromatic aldehydes. The reaction was carried out in methanol medium in the presence of an alkaline agent. High resolution 1H and 13C NMR resonance assignments and conformational assignments were carried out for four 3- arylidene or hydroxyarylmethyl and 3-arylidene-5- hydroxyarylmethyl substituted piperidine-4-ones (1-4). As a result of the initial aldol condensation of piperidine-4-ones with aromatic aldehydes an aryloxymethyl group in the intermediate compound can have both an equatorial and axial position. Conformation of a conjugated system proved to be electronically effected by the presence of nitrogen atom in the heterocycle. At the same time, conformation peculiarities of α, β-unsaturated ketones under study are developed at the stage of their synthesis. This is explained by the fact that in the course of the reaction there appears a new sp2-centre, this resulting in our case in the change of the conformation of “a chair”. There takes place flattening of the structure and fixation of s-cis conformation. Furfurilidene substituent is conjugated with a carbonyl group, there forms a planar structure including 2, 3, 4 and 5 atoms of hydrogen of piperidine cycle and furfurilidene substituent and there exist two isomers with cis- (A) and trans- (B) position of a furyl ring at double bond in relation to a carbonyl group.

Over expression of nucleotide pyrophosphatase (NPPs) activity is associated with chondrocalcinosis, osteoarthritis, type 2 diabetes, neurodegenerative diseases, allergies and cancer metastasis. The potential of NPPs inhibitors as therapeutic agents, and the scarceness of their structure–activity relationship, encouraged us to develop new NPP inhibitors. Specifically, 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolopyrimidine and its corresponding 6-fluoro derivatives were synthesized via a Suzuki–Miyaura reaction. The cross-coupling reaction with different arylboronic acids gave desired coupling products in good to excellent yields and showed wide functional group tolerance. Furthermore, all compounds were investigated for their potential to inhibit two families of ecto-nucleotidases, i.e. nucleoside triphosphate diphosphohydrolases (NTPDase) and NPPs. Interestingly, our compounds were identified as selective inhibitors of NPPs. Among derivatives 5a–5i, compound 5i (IC50 ± SEM = 0.39 ± 0.01 μM) was found to be the most potent inhibitor of h-NPP1 and compound 5h (IC50 ± SEM = 1.02 ± 0.05 μM) was found to be the most potent inhibitor of h-NPP3. Similarly, for fluorinated thiadiazolopyrimidones, derivative 6e (IC50 ± SEM = 0.31 ± 0.01 μM) exhibited the best inhibition of NPP1 and it was found that this compound exhibited ≈28 fold improvement in inhibitory potential as compared with the reference control i.e. Suramin (IC50 ± SEM = 8.67 ± 1.3 μM). Moreover, homology modelling and molecular docking studies of both inhibitors were carried out to suggest the putative binding mode of inhibitors with the respective enzyme i.e. h-NPP1 and h-NPP3.

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.