Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1-9 displayed good potency (EC50T. cruzi amastigote <1 µM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32-64 µM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.

Chagas Disease Drug Discovery in Latin America-A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021.

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing.

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol.

A general procedure for the synthesis of 2-substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido alcohols promoted by trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of several hitherto unreported seven-membered iminothioethers bearing 2-aryl, alkenyl, aralkyl and alkyl substituents. The cyclodehydration reaction is likely to involve an SN2-type displacement and affords good to excellent yields of the desired heterocycles in very short reaction times.

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids.

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

Microwave-Assisted Synthesis of 2-Aryl-2-oxazolines, 5,6-Dihydro-4H-1,3-oxazines, and 4,5,6,7-Tetrahydro-1,3-oxazepines.

The first general procedure for the synthesis of 5- to 7-membered cyclic iminoethers by microwave-assisted cyclization of ω-amido alcohols promoted by polyphosphoric acid (PPA) esters is presented. 2-Aryl-2-oxazolines and 5,6-dihydro-4H-1,3-oxazines were efficiently prepared using ethyl polyphosphate/CHCl3. Trimethylsilyl polyphosphate in solvent-free conditions allowed for the synthesis of hitherto-unreported 4,5,6,7-tetrahydro-1,3-oxazepines. The method involves good to excellent yields and short reaction times.The reaction mechanism and the role of PPA esters were investigated in a chiral substrate.

Microwave-assisted cyclizations promoted by polyphosphoric acid esters: a general method for 1-aryl-2-iminoazacycloalkanes.

The first general procedure for the synthesis of 5 to 7-membered 1-aryl-2-iminoazacycloalkanes is presented, by microwave-assisted ring closure of ω-arylaminonitriles promoted by polyphosphoric acid (PPA) esters. 1-Aryl-2-iminopyrrolidines were easily prepared from the acyclic precursors employing a chloroformic solution of ethyl polyphosphate (PPE). The use of trimethylsilyl polyphosphate (PPSE) in solvent-free conditions allowed for the synthesis of 1-aryl-2-iminopiperidines and hitherto unreported 1-aryl-2-iminoazepanes. The cyclization reaction involves good to high yields and short reaction times, and represents a novel application of PPA esters in heterocyclic synthesis.