Mini Reviews in Medicinal Chemistry - Volume 20, Issue 17, 2020

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

Diabetes mellitus (DM) is a metabolic disease, and diabetes patients have long-term higher blood sugar levels than standard. Most people with diabetes have complications that greatly affect their standard of living. Patients with type 2 DM occupy the vast majority of all diabetes patients. Glucagonlike peptide-1 (GLP-1) secreted by intestinal enteroendocrine L-cells is a small molecule polypeptide, which is glucose concentration-dependent and can effectively reduce blood glucose concentration. Dipeptidyl peptidase-4 (DPP-4) is an important target for the treatment of type 2 DM because it can degrade GLP-1. DPP-4 inhibitors can enhance the blood glucose lowering effect of GLP-1 by inhibiting DPP-4. This article summarizes the development of DPP-4 inhibitors from 2015 to 2019, and can provide helpful information for the discovery of novel DPP-4 inhibitors in the future.

Aryloxyphenylpiperazinylpropanols are a group of compounds exhibiting a wide range of biological activities, affecting the central nervous system and many cardiovascular mechanisms among them. As cardiovascular agents, aryloxyphenylpiperazinylpropanols work as antihypertensives, antiarrhythmics, cardiotonics or antiaggregants. The mechanism of action is almost always an α1-adrenolytic or combined α1- and β-adrenolytic effect, but sometimes other mechanisms (e.g., Ca²⁺ antagonism or phosphodiesterase inhibition) can positively participate. In some cases, compounds with a small modification of the connecting chain also exhibit the desired cardiovascular effects. Several studies dealt with chirality of aryloxyphenylpiperazinylpropanols and determined the differences between the particular activities of racemic and enantiomeric compounds.

Protein kinases are conserved enzymes that catalyse the phosphorylation process in cells. They are recognized as the targets for many diseases. The FDA has approved many kinase inhibitors for the treatment of cancer and confirmed kinases as relevant targets for drug discovery. Major approved drugs are ATP competitive reversible non-covalent inhibitors that achieve selectivity by recognition of specific binding pockets of targeted kinases. In recent years, scientists have paid attention on developing irreversible covalent kinase inhibitors to achieve better selectivity, less toxicity and side effects. Since 2013, seven Irreversible Kinase Inhibitors (IKIs), including; afatinib, ibrutinib, neratinib, dacomitinib, osimertinib, acalabrutinib and zanubrutinib have been approved by the FDA for treatment of severe diseases, like; Metastatic Non-Small Cell Lung Cancer (NSCLC), Mantle Cell Lymphoma (MCL) and HER2-positive breast cancer. These inhibitors target the cysteine residues of kinases. Many IKIs that target cysteine residues are in clinical trials for different diseases and are yet to be approved. We have reviewed the research done and efforts made for finding novel cysteine targeted IKIs as drugs in the recent years.

Cancer is the second life-threatening disease worldwide, and it resulted in around 9.6 million deaths globally in 2018. The multidrug-resistant cancers and non-selectivity create an urge for the development of novel anticancer drugs with a diverse mechanism of action. Coumarin is one of the most widely used scaffolds for the development of highly effective anticancer agents. It has versatile anticancer profiles with diverse mechanisms to inhibit tumor progression. The facile synthetic strategies are also favoured for target-based coumarin derivatives. Structural Activity Relationship (SAR) studies determine anticancer potentials with minimal side effects through the substitution pattern of coumarin. A number of coumarin derivatives have been developed against the Galectin-1 (Gal-1), Carbonic anhydrases (CAs), Tubulin protein, and other essential targets for the treatment in cancer therapy. Therefore, in this review, we have mainly focused on different target based coumarin derivatives, and synthetic strategies.

Imaging agents are crucial in diagnosing diseases. Ultrasmall lanthanide oxide (Ln2O3) nanoparticles (NPs) (Ln = Eu, Gd, and Dy) are promising materials as high-performance imaging agents because of their excellent magnetic, optical, and X-ray attenuation properties which can be applied as magnetic resonance imaging (MRI), fluorescence imaging (FI), and X-ray computed tomography (CT) agents, respectively. Ultrasmall Ln2O3 NPs (Ln = Eu, Gd, and Dy) are reviewed here. The reviewed topics include polyol synthesis, characterization, properties, and biomedical imaging applications of ultrasmall Ln2O3 NPs. Recently published papers were used as bibliographic databases. A polyol method is a simple and efficient one-pot synthesis for preparing ultrasmall Ln2O3 NPs. Ligand-coated ultrasmall Ln2O3 NPs have good colloidal stability, biocompatibility, and renal excretion ability suitable for in vivo imaging applications. Ultrasmall Eu2O3 NPs display photoluminescence in the red region suitable for use as FI agents. Ultrasmall Gd2O3 NPs have r1 values higher than those of commercial molecular contrast agents and r2/r1 ratios close to 1, which make them eligible for use as T1 MRI contrast agents. Ultrasmall Dy2O3 NPs exhibit high r2 and negligible r1 values, which make them suitable for use as T2 MRI contrast agents. All ultrasmall Ln2O3 NPs have high X-ray attenuation powers which make them suitable for use as CT contrast agents. Unmixed, mixed, or doped ultrasmall Ln2O3 NPs with different Ln are extremely useful for in vivo imaging applications in MRI, CT, FI, MRI-CT, MRI-FI, CT-FI, and MRI-CT-FI.

Postoperative Cognitive Dysfunction (POCD) refers to the condition of neurocognitive decline following surgery in a cognitive and sensory manner. There are several risk factors, which may be life-threatening for this condition. Neuropsychological assessment of this condition is very important. In the present review, we discuss the association of apolipoprotein epsilon 4 (APOE 4) and few miRNAs with POCD, and highlight the clinical importance for prognosis, diagnosis and treatment of POCD. Microarray is a genome analysis that can be used to determine DNA abnormalities. This current technique is rapid, efficient and high-throughout. Microarray techniques are widely used to diagnose diseases, particularly in genetic disorder, chromosomal abnormalities, mutations, infectious diseases and disease-relevant biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are widely found distributed in eukaryotes. Few miRNAs influence the nervous system development, and nerve damage repair. Microarray approach can be utilized to understand the miRNAs involved and their pathways in POCD development, unleashing their potential to be considered as a diagnostic marker for POCD. This paper summarizes and identifies the studies that use microarray based approaches for POCD analysis. Since the application of microarray in POCD is expanding, there is a need to review the current knowledge of this approach.

α-Glucosidase plays an important role in carbohydrate metabolism and is an attractive drug target for the treatment of diabetes, obesity and other related complications. Currently, acarbose, miglitol and voglibose have been approved by the FDA for the treatment of diabetes by oral α-glucosidase inhibitors. With the development of anti-diabetic drugs, the emergence of novel drugs with various chemotypes has overshadowed α-glucosidase inhibitors. Since the 1990s, the FDA has not approved new chemical entities against α-glucosidase, which has resulted in restricted clinical medication. Nevertheless, this type of inhibitors possess several unparalleled advantages over other drugs, especially mild side effects (non-systemic gastrointestinal side effects and occasional allergic reactions). Additionally, α-glucosidase inhibitors for monotherapy or in combination with other drugs have been proved to be a feasible approach for the treatment of diabetes. In the last decade, the discovery of natural or synthetic indole derivatives possessing the inhibitory activity of α-glucosidase has received great attention. Herein, we have summarized indoles as inhibitors of α-glucosidase activity, their mechanism of action, synthetic methodologies and structure-activity relationships. Moreover, we have compared the inhibitory potencies of all compounds under their corresponding positive control as well as oral absorption in silico evaluated by tPSA. This review will provide a medium on which future drug design and development for the treatment of diabetes may be modeled as many drug candidates with present great potential as effective anti-diabetic chemotherapy.