Tenebrio molitor as a Simple and Cheap Preclinical Pharmacokinetic and Toxicity Model

The progression of drugs into clinical phases requires proper toxicity assessment in animals and the correct identification of possible metabolites. Accordingly, different animal models are used to preliminarily evaluate toxicity and biotransformations. Rodents are the most common models used to preliminarily evaluate the safety of drugs; however, their use is subject to ethical consideration and elevated costs, and strictly regulated by national legislations. Herein, we developed a novel, cheap and convenient toxicity model using Tenebrio molitor coleoptera (TMC). A panel of 15 drugs-including antivirals and antibacterials-with different therapeutic applications was administered to TMC and the LD50 was determined. The values are comparable with those already determined in mice and rats. In addition, a TMC model was used to determine the presence of the main metabolites and in vivo pharmacokinetics (PK), and results were compared with those available from in vitro assays and the literature. Taken together, our results demonstrate that TMC can be used as a novel and convenient preliminary toxicity model to preliminarily evaluate the safety of experimental compounds and the formation of main metabolites, and to reduce the costs and number of rodents, according to 3R principles

Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer

Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target

Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family

17openPreventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.openTintori, Cristina; Brai, Annalaura; DASSO LANG, MARIA CHIARA; Deodato, Davide; Greco, Antonia Michela; Bizzarri, Bruno Mattia; Cascone, Lorena; Casian, Alexandru; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Vanham, Guido; Ceresola, Elisa; Canducci, Filippo; Ariën, Kevin K.; Botta, MaurizioTintori, Cristina; Brai, Annalaura; DASSO LANG, MARIA CHIARA; Deodato, Davide; Greco, Antonia Michela; Bizzarri, Bruno Mattia; Cascone, Lorena; Casian, Alexandru; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Vanham, Guido; Ceresola, Elisa; Canducci, Filippo; Ariën, Kevin K.; Botta, Maurizi

A Greener Technique for Microwave-Assisted O-Silylation and Silyl Ether Deprotection of Uridine and Other Substrates

A single clean, good-yielding, environment-friendly microwave-assisted procedure for O-silylation of uridine with tert-butyldimethylsilyl chloride (TBDMSCl), 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) and potassium nitrate as catalyst under solvent-free conditions is reported. Subsequent silyl ether deprotection is accomplished with a reusable acidic resin via microwave irradiation. Both the silylation and desilylation protocols have been applied to a panel of alcohols of pharmaceutical interest

A Greener Technique for Microwave-Assisted O-Silylation and Silyl Ether Deprotection of Uridine and Other Substrates

A single clean, good-yielding, environment-friendly microwave-assisted procedure for O-silylation of uridine with tert-butyldimethylsilyl chloride (TBDMSCl), 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) and potassium nitrate as catalyst under solvent-free conditions is reported. Subsequent silyl ether deprotection is accomplished with a reusable acidic resin via microwave irradiation. Both the silylation and desilylation protocols have been applied to a panel of alcohols of pharmaceutical interest

Protein-protein interactions and human cellular cofactors as new targets for HIV therapy

Two novel approaches for the development of new drugs against AIDS are summarized each leading to the achievement of important discoveries in anti-HIV therapy. Despite the success of HAART in reducing mortality, resistant strains continue to emerge in the clinic, underscoring the importance of developing next-generation drugs. Protein protein interactions and human cellular cofactors represent the new targets of tomorrow in HIV research. The most relevant results obtained in the last few years by the two new strategies are described herein

An alternative synthetic approach for the synthesis of biologically relevant 1,4-disubstituted pyrazolo[3,4-d]pyrimidines

A versatile approach for the synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines has been developed. Starting from commercially available allopurinol, TBAF mediated N1-functionalization and subsequent C4 nucleophilic substitution, under microwave assisted- or standard heating conditions, granted access to highly functionalized pyrazolo[3,4-d]pyrimidines of potential biological interest