Role of polypill in cardiovascular prevention and treatment.

Cardiovascular diseases (CVD) remain the leading cause of mortality globally and require innovative strategies for effective prevention and treatment. The polypill concept, which integrates multiple cardioprotective agents into a single dosage form, has emerged as a promising approach to improve adherence and simplify the management of cardiovascular risk factors. We review clinical trials and observational studies evaluating the impact of the polypill on reducing the incidence of major cardiovascular events (MACEs), its influence on medication adherence, and its potential to fill treatment gaps in diverse populations. Also of note are the pharmacoeconomic implications of the widespread use of the polypill, particularly in low- and middle-income countries where the burden of cardiovascular disease is increasing. Although the polypill demonstrates a favorable profile in improving therapeutic compliance and reducing cardiovascular risk factors, debates persist regarding its efficacy compared to individualized treatment regimens. This review summarizes the current evidence on the efficacy, safety, and cost-effectiveness of the polypill in CVD primary and secondary prevention. Furthermore, potential challenges in implementing the polypill strategy include tailoring the components to patient-specific risk profiles and the need for robust evidence from large-scale randomized controlled trials to substantiate its long-term benefits.

A Personalized Approach for Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) includes coronary embolism, dissection, spasm and microvascular dysfunction, as well as plaque rupture or erosion (causing < 50% stenosis). In the most recent studies, events that can be classified as MINOCA account for approximately 6-8% of all diagnoses of acute myocardial infarction (AMI). Clinical suspect may suggest the need for additional diagnostic procedures beyond the usual coronary angiography, such as cardiac imaging or provocative tests. Cardiac magnetic resonance (CMR) is essential for both validating the diagnosis and ruling out other conditions with a comparable clinical presentation. The prognosis is not as good as previously believed; rather, it is marked by morbidity and mortality rates comparable to those of other types of AMI. Identification of the underlying causes of MINOCA is recommended by current guidelines and consensus documents in order to optimize treatment, enhance prognosis, and encourage prevention of recurrent myocardial infarction. In this narrative review, we have outlined the various causes of MINOCA and their specific therapies in an attempt to identify a personalized approach to its treatment.

Current Data and Future Perspectives on Patients with Atrial Fibrillation and Cancer.

Atrial fibrillation (AF) is an increasingly recognized comorbidity in patients with cancer. Indeed, cancer patients have a significantly higher incidence of AF than that observed in the general population. A reciprocal relationship between these two diseases has been observed, as much as some assume AF to be a marker for occult cancer screening, especially in older adults. The pathophysiological mechanisms are many and varied, including the underlying pro-inflammatory state, specific treatments (chemo- and radiotherapy), and surgery. The therapeutic management of patients with cancer and AF involves the same rhythm and frequency control strategies as the general population; however, the numerous interactions with chemotherapeutics, which lead to a significant increase in side effects, as well as the extreme fragility of the patient, should be considered. Anticoagulant therapy is also a complex challenge to address, as bleeding and stroke risk scores have not been fully assessed in this subpopulation. Furthermore, in large studies establishing the efficacy of direct oral anticoagulants (DOACs), cancer patients have been underrepresented. In this review, we elaborate on the mechanisms linking AF to cancer patients with a particular focus on the therapeutic challenges in this population.

Synthesis and biological characterization of 3-(imidazol-1-ylmethyl)piperidine sulfonamides as aromatase inhibitors.

The most frequently used treatment for hormone receptor positive breast cancer in post-menopausal women are aromatase inhibitors. In order to develop new aromatase inhibitors, we designed and synthesized new imidazolylmethylpiperidine sulfonamides using the structure of the previously identified aromatase inhibitor SYN 20028567 as starting lead. By this approach, three new aromatase inhibitors with IC50 values that are similar to that of letrozole and SYN 20028567 were identified.

Computer-aided Molecular Design of Compounds Targeting Histone Modifying Enzymes.

Growing evidences show that epigenetic mechanisms play crucial roles in the genesis and progression of many physiopathological processes. As a result, research in epigenetic grew at a fast pace in the last decade. In particular, the study of histone post-translational modifications encountered an extraordinary progression and many modifications have been characterized and associated to fundamental biological processes and pathological conditions. Histone modifications are the catalytic result of a large set of enzyme families that operate covalent modifications on specific residues at the histone tails. Taken together, these modifications elicit a complex and concerted processing that greatly contribute to the chromatin remodeling and may drive different pathological conditions, especially cancer. For this reason, several epigenetic targets are currently under validation for drug discovery purposes and different academic and industrial programs have been already launched to produce the first pre-clinical and clinical outcomes. In this scenario, computer-aided molecular design techniques are offering important tools, mainly as a consequence of the increasing structural information available for these targets. In this mini-review we will briefly discuss the most common types of known histone modifications and the corresponding operating enzymes by emphasizing the computer-aided molecular design approaches that can be of use to speed-up the efforts to generate new pharmaceutically relevant compounds.

Access to N-thioalkenyl and N-(o-thio)aryl-benzimidazol-2-ones by ring opening of thiazolobenzimidazolium and benzimidazobenzothiazolium salts and C-O bond cleavage of an alkoxide.

We report herein the synthesis of highly functionalized 1,3-dihydro-2H-benzimidazol-2-ones via a ring opening of thiazolo[3,2-a]benzimidazolium or benzimidazo[2,1-b][1,3]benzothiazol-6-ium salts and an unusual C-O bond cleavage of an alkoxide. A large variety of benzimidazolones bearing an original N-thioalkenyl or N-(o-thio)aryl group was obtained in high yields. The developed chemistry provides efficient and rapid access to the privileged benzimidazol-2-one scaffold.

Physicochemical modifications of histones and their impact on epigenomics.

The study of histone post-translational modifications (PTMs) has made extraordinary progress over the past few years and many epigenetic modifications have been identified and found to be associated with fundamental biological processes and pathological conditions. Most histone-modifying enzymes produce specific covalent modifications on histone tails that, taken together, elicit complex and concerted processes. An even higher level of complexity is generated by the action of small molecules that are able to modulate pharmacologically epigenetic enzymes and interfere with these biochemical mechanisms. In this article, we provide an overview of histone PTMs by reviewing and discussing them in terms of their physicochemical properties, emphasizing these concepts in view of recent research efforts to elucidate epigenetic mechanisms and devise future epigenetic drugs.

Novel phenyl(thio)ureas bearing (thio)oxothiazoline group as potential BACE-1 inhibitors: synthesis and biological evaluation.

We report the synthesis and the ß-site amyloid precursor protein cleaving enzyme-1 inhibitory properties of novel phenyl(thio)ureas bearing 2-(thio)oxothiazoline derivatives. A library of analogues was prepared according to specific synthetic schemes and the inhibitory activity was monitored using a fluorescence resonance energy transfer assay. Several analogues show potent inhibitory activities ranging between 1 and 0.01 µM and the activity is related to the NH acidity of the (thio)urea motif. Our results illustrate once again the close relationship between molecular recognition, complexation of the active site in enzymatic system, and organocatalysis utilizing explicit hydrogen bonding.

Immunoproteasome in cancer and neuropathologies: a new therapeutic target?

Immunoproteasome is an emerging biological target that constitutes a key element not only in antigen presentation but also in T cell and cytokine regulation as well as cellular homeostasis. Respect to standard proteasome, the inducible expression and different sensitivity towards activity modulators of immunoproteasome render it a potential therapeutic target for tumours and central nervous system diseases. In this review we report the cutting edge studies for understanding when immunoproteasome expression is induced and how it regulates pivotal pathways involved in tumours and neuropathologies, including apoptosis and inflammation. We emphasize its role as a new pharmacological target by describing the recent medicinal chemistry efforts aimed at design selective small-molecule modulators of both standard- and immuno-proteasome forms. Finally, we also present an in silico model of the human immunoproteasome structure by the major molecular differences with the 20S standard proteasome and discuss the perspective for the design of novel specific smallmolecule modulators for the different proteasome isoforms.

Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives.

Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.

3-(2-aminophenyl)-4-methyl-1,3-thiazole-2(3H)-thione as an ecofriendly sulphur transfer agent to prepare alkanethiols in high yield and high purity.

A new process is described for preparing very pure linear alkanethiols and linear alpha,omega-alkanedithiols using a sequential alkylation of the title compound, followed by a ring closure to quantitatively give the corresponding 3-methyl[1,3]thiazolo[3,2-a]-[3,1]benzimidazol-9-ium salt and the alkanethiol derivative under mild conditions. The alkanethiol and the heteroaromatic salt are easily separated by a simple extraction process. The intermediate thiazolium quaternary salts resulting from the first reaction step can be isolated in quantitative yields, affording an odourless protected form of the thiols.

Synthesis, chiral separation, and absolute configuration of bis-(N-aryl) atropisomeric triads: 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene.

In this work, a series of 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene has been prepared. These atropisomeric molecular triads were exclusively found to exist in the anti-form. They were separated into enantiomers by liquid chromatography on a chiral support. The absolute configurations of the enantiomers were determined using a chemical correlation method together with chiral chromatography. The barriers to interconversion of the enantiomers were determined.

Non-racemic atropisomeric (thio)ureas as neutral enantioselective anion receptors for amino-acid derivatives: origin of smaller Kass with thiourea than urea derivatives.

The synthesis of a limited series of non-racemic atropisomeric 1-(2-(4-methyl-2-thioxothiazol-3(2H)-yl)phenyl)-3-(hetero)aryl-(thio)ureas is described. Using NMR titration experiments monitoring the shift of the two NH of the (thio)urea and the C-5 hydrogen of the heterocycle, the binding constants for some optically pure (thio)-ureas with the enantiomers of N-protected amino acid tetrabutylammonium salts were determined in CD3CN. The obtained enantioselectivities were modest. Contrary to what was expected on the basis of the NH acidity in thiourea versus urea group, the association constants were smaller with the thiourea than with the corresponding urea. X-ray data, DFT calculations, and NMR provided the explanation of that unexpected behavior: the urea presents a pre-organized (Z,Z) conformation suitable for a double hydrogen bond with the carboxylate anion, the thiourea presents a (Z,E) conformation, which must be reorganized in a constrained (Z,Z) conformation in the complex. An intramolecular hydrogen bond between one NH and the thiocarbonyl group of the heterocycle, which is present in the thiourea and absent in the urea, might also contribute to the smaller K(ass) for the thiourea. The possible implication of these observations in the field of bifunctional organocatalysis is briefly discussed.

New route to 3-alkylthiazolo[3,2-a]benzimidazole derivatives.

3-Alkyl-thiazolo[3,2-a]benzimidazole derivatives are obtained in high yields via the corresponding 4-alkyl-N-3-(2-aminophenyl)-thiazoline-2-thiones which are easily prepared from 1,2-diaminobenzene, CS(2) and halogenoketones. This new route compares advantageously with the classical mercaptobenzimidazole routes in term of simplicity,isolated yields and availability of the starting materials.