Current Medicinal Chemistry - Volume 29, Issue 17, 2022

Despite the countless efforts made in the last decades, malaria and neglected tropical diseases remain a high-impact health problem in developing countries. Malaria is one of the most severe parasitic diseases, with over 200 million cases and 400,000 deaths in 2019. Parasitic diseases caused by trypanosomatidae, namely Human African Trypanosomiasis, Chagas disease, and leishmaniasis, register the highest rates of mortality amongst all the neglected tropical diseases. In this scenario, chemotherapy remains the first strategy, which aims to control and eliminate these diseases. However, the use of outdated, unsafe, and poorly effective drugs, together with the onset of resistance, prompted the researchers to identify new and valid targets. The innovative idea, aimed at the development of multi-target ligands addressing two different targets playing key roles in parasite survival, could represent a valuable strategy. Thanks to this approach, the wellknown limitations characterizing the antiparasitic drugs, such as toxicity, rapid resistance onset and narrow spectrum of action, could be overcome. In this review, we now describe the most recent multi-target ligands endowed with antiparasitic effects reported in the literature, focusing our attention on their binding with the targets, inhibitory activities, and potential therapeutic applications.

Colorectal cancer (CRC) comprises a heterogeneous group of gastrointestinal tract tumors. It is a multifactorial disease, and a plethora of distinct factors are involved in its pathogenesis and pathophysiology. The development of CRC is not limited to genetic changes, but epigenetic and environmental factors are also involved. Among the epigenetic factors, histone deacetylases (HDACs), a group of epigenetic enzymes that regulate gene expression, have been reported to be over-expressed in CRC. HDACs and their inhibitors seem to play an important role in the molecular pathophysiology of CRC. The aim of this review was to define the role of HDAC inhibitors as potential anticancer agents against CRC.

LIMK1 and LIMK2 are involved in the regulation of cellular functions that depend on the dynamics of actin cytoskeleton. Disregulation of LIM kinases has been associated with diseases, such as tumor progression and metastasis, viral infection, and ocular diseases. Motivated by this, numerous studies have been carried out to discover small organic molecules capable of inhibiting LIM kinase effectively and selectively. In this review, a comprehensive survey of small organic molecules for LIM kinase inhibitors is reported, together with SAR study results, and the synthesis of these inhibitors.

This article aims at reviewing celecoxib as a potential inhibitor in the treatment of inflammatory diseases. The enzyme cyclooxygenase (COX) predominantly has two isoforms called cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The former plays a constitutive role related to homeostatic effects in renal and platelets, while the latter is mainly responsible for the induction of inflammatory effects. Since COX-2 plays an important role in the pathogenesis of inflammatory diseases, it has been signaled as a target for the planning of anti-inflammatory intermediates. Many inhibitors developed and planned for COX-2 inhibition have presented side effects to humans, mainly in the gastrointestinal and/or cardiovascular tract. Therefore, it is necessary to design new potential COX-2 inhibitors, which are relatively safe and have no side effects. In this sense, celecoxib is the only potent, selective COX-2 inhibitor that is still commercially available (within the “coxib” family). Thus, celecoxib became a commercial prototype inhibitor for the development of anti-inflammatory agents for the COX-2 enzyme. This review provides inhibition highlights that should provide a structural basis for the design of promising new non-steroidal anti-inflammatory drugs (NSAIDs), which act as COX-2 inhibitors with lesser side effects on the human body.

Tyrosine kinases expressed by BCR-ABL fusion genes can cause changes in cell proliferation, adhesion, and survival properties, which are the main causes of chronic myelogenous leukemia (CML). Inhibiting the activity of BCR-ABL tyrosine kinase has become one of the effective methods for the treatment of chronic myelogenous leukemia. Initially, imatinib was the first small molecule of BCR-ABL tyrosine kinases inhibitors (TKIs) for the effective treatment of chronic myelogenous leukemia. Later, due to the emergence of various BCR-ABL mutations, especially T315I mutation, imatinib developed strong resistance. The second-generation kinase inhibitors dasatinib and nilotinib were able to overcome most of the mutation resistance but not T315I mutations. Therefore, in order to further overcome the problem of drug resistance, new types of KTIs such as flumatinib and radotinib have been developed, providing more options for clinical treatment. Some new drugs have entered clinical trials. In this review, two new BCRABL inhibitors (flumatinib and radotinib) and five new BCR-ABL inhibitors have been introduced into the clinical market in recent years. We reviewed their research status, synthesis methods, and clinical applications.

The diseases affecting the Central Nervous System (CNS) can have varied etiopathology, but they have in common silent progression, global incidence, and significant impacts on the quality of life of patients and public health systems. With the advance of biomedicine and pharmaceutical technology, new and more modern diagnostic methods and treatments were developed, repurposing the use of drugs currently available for the treatment of CNS diseases. An attractive approach is the use of alternative drug delivery platforms, such as nanocarriers, and less invasive administration routes, such as the noseto- brain, extensively explored for the delivery of drugs into the CNS. Despite many promising results, the nose-to-brain route has some physiological limitations that make it difficult to deliver drugs satisfactorily to exert therapeutic activity in the CNS. To overcome these limitations, nanostructured systems with mucoadhesive properties have stood out over the last few years in pharmaceutical R In this review; we discuss how the noseto- brain route limitations can influence the delivery of drugs to the CNS and highlight the benefits that mucoadhesion can bring to these nanostructured systems. The main findings in the literature are brought together and discussed critically, focusing on how mucoadhesion can improve the biopharmaceutical properties of molecules used in the clinic, as well as their biological performance. Finally, conclusions are drawn about the points of strength of mucoadhesive nanosystems and the points that still need attention to successfully use the nose-to-brain route for the treatment of diseases that affect the CNS.

Exosomes are a heterogeneous group of nano-sized natural membrane vesicles released from various cells and exist in body fluids. Different from the previous understanding of the function of exosomes as “garbage bins”, exosomes act as carriers with many kinds of bioactive molecules (e.g., proteins, lipids, and nucleic acids) to play an important role in cell-cell communication. Growing evidence in recent years has suggested that exosomes also play some roles in the pathogenesis, diagnosis, and treatment modalities of some brain diseases, including ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and brain cancers. Exosomes as therapeutic drug carriers for brain drug delivery have received extensive attention as well as exosomes can overcome the blood-brain barrier (BBB). However, the low targeting ability and size-dependent cellular uptake of native exosomes could profoundly affect the delivery performance of exosomes. Recent studies have indicated that engineered exosomes can increase the drug uptake efficiency and the subsequent drug efficacy. In the present paper, we will briefly introduce the engineering methods and applications of engineered exosomes in the treatment of brain diseases, and then focus on discussing the advantages and challenges of exosome- based drug delivery platforms to further enrich and boost the development of exosomes as a promising drug delivery strategy for brain diseases.

Background: Ethyl glucuronide (EtG) is a metabolite of ethanol used as a marker of alcohol drinking and is identified in urine. Gestational alcohol drinking harms the fetus, so disclosing any form of use and abuse of this substance during pregnancy is crucial. Many discovery methods have been planned to overcome this question, including using screening questionnaires as the AUDIT-C, T-ACE/TACER-3, and TWEAK. Aim: The aim and novelties of this study were to compare biochemical data from urinary EtG assays (cut-off 100 ng/mL for risking drinking behavior) with the outcome of questionnaires and of a food diary routinely used in our hospital; moreover, for the first time, we analyzed in pregnant women the EtG values normalized by the amount of creatinine excreted according to methods previously established. Methods: Random urine samples were collected from 309 pregnant women immediately after being interviewed. EtG was quantified using an enzyme immunoassay, and urinary creatinine was assessed using an enzymatic colorimetric method. Women who had not exhaustively answered one of the questionnaires or refused to provide urine samples were excluded. Finally, 309 women were considered for this study. Urine creatinine measurements were performed to determine if urine dilution might have resulted in false negatives in the challenge study. In order to accomplish this objective, as urinary creatinine concentrations are, on average, approximately 1 mg/mL, we used a normalized value of 100 ng EtG/mg Creatinine. Results: Our data show that 20.4% of the pregnant women in the study were over the established normalized cut-off value. Poor to null concordance (unweighted k < 0.2) was found between EtG data and the screening interviews showed, on average, lower levels of alcohol consumption. Conclusion: This study provides evidence that the assessment of maternal alcohol consumption during pregnancy, only indirectly estimated with questionnaires and food diary, can produce misleading results.