Current Medicinal Chemistry - Volume 28, Issue 29, 2021

This article presents a simplified view of integrins with emphasis on the α4 (α4β1/VLA-4) integrin. Integrins are heterodimeric proteins expressed on the cell surface of leukocytes that participate in a wide variety of functions, such as survival, growth, differentiation, migration, inflammatory responses, tumour invasion, among others. When the extracellular matrix is degraded or deformed, cells are forced to undergo responsive changes that influence remodelling during physiological and pathological events. Integrins recognize these changes and trigger a series of cellular responses, forming a physical connection between the interior and the outside of the cell. The communication of integrins through the plasma membrane occurs in both directions, from the extracellular to the intracellular (outside-in) and from the intracellular to the extracellular (inside-out). Integrins are valid targets for antibodies and small-molecule antagonists. One example is the monoclonal antibody natalizumab, marketed under the name of TYSABRI®, used in the treatment of recurrent multiple sclerosis, which inhibits the adhesion of α4 integrin to its counter-receptor. α4β1 Integrin antagonists are summarized here, and their utility as therapeutics are also discussed.

Multidrug resistance in bacteria is a major threat to global health and the effective prevention and treatment of infections. The urgent need for novel antimicrobial agents, together with the increasing challenges in discovering and developing effective antibiotics, has inspired new approaches and strategies to circumvent antibiotic resistance. Despite this effort, the difficulty in cell-penetration and delivery of antibiotics into bacterial cells remains the bottleneck for both traditional and non-traditional antibacterial agents to realize their full potential. Recently, cell-penetrating peptides (CPPs) have attracted considerable attention as low-toxicity carriers, promising the improvement of the low biological activity of traditional antimicrobial agents. CPPs are now extensively used to deliver various antibiotics, including recently developed agents, such as antisense oligonucleotides (ASOs). The conjugation of CPPs to antimicrobial peptides (AMPs) can also greatly enhance antibacterial activity and may present an effective approach for developing novel antimicrobial agents. This review discusses the characteristics, designing strategies, and recent progress in the development and application of antimicrobial CPPs as potent antibacterial agents against multidrug-resistant bacteria.

The last decade has been characterized by the development and approval of pretomanid and delamanid, which are nitroimidazole based drugs for multidrug -resistant tuberculosis. This attracted renewed attention to the nitroheterocyclic scaffolds as a source of safe and efficient antimicrobial agents. While the primary focus is still on nitrofurans and nitroimidazoles, well known as bioreducible prodrugs, a number of studies have been published on other 5-membered nitroheteroaromatic compounds. The latter not only show promising antimicrobial activity but also demonstrate modes of action different from the conventional reductive activation of the nitro group. Considering the potential of these efforts to impact the continuing race against drug-resistant pathogens, herein we review non-furan/imidazole-based 5-membered nitroheteroaromatics investigated as antimicrobial agents in 2010-2020.

Neurological disorders (NDs) comprise a broad range of diseases affecting both central and peripheral nervous systems. These complex multifactorial diseases have a high rate of mortality all over the world, particularly in aged people. Today, new evidence drove our attention to the notable role of noncoding RNAs (ncRNAs) in the progression of NDs. Remarkably, recent studies showed that there are close communication networks among RNA transcripts such as mRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and pseudogenes for regulating each other’s expression through competing for shared sequences in microRNAs (miRs). This concept is a new area of ongoing research recognized as competing endogenous RNA (ceRNA) hypothesis. CeRNAs are novel regulatory molecules in a wide range of biological stages and pathological contexts. Indeed, the disruption of ceRNA networks (ceRNETs) may affect neural development genes and induce neuropathological changes leading to the development of NDs. Because of this, identifying the correlation of ceRNETs with NDs will open a new window for expanding our knowledge about this field of science, as well as creating novel roads for developing specific diagnostic biomarkers for NDs management. Owing to these unique features, exploring the exact role of ceRNAs is a hot topic in NDs investigations. Hence, in this review, we will summarize the evidence supporting ceRNETs in the regulation of NDs-related gene expression.

Lupus nephritis (LN) is severe renal comorbidity associated with systemic lupus erythematosus (SLE), a complex autoimmune disorder with high morbidity and mortality. Diagnosis and monitoring of LN patients still rely on renal biopsy, a procedure that exposes patients to a variety of risks and is not capable of providing longitudinally information about disease prognosis. In this review, we summarized current data of recent promising biomarkers developed in the precision medicine era, particularly under genomic, transcriptomic, proteomic, and metabolomic techniques. Genome-wide association studies have been evaluating the role of endogenous elements beyond the autoimmunity in LN. Transcriptomic methods, including single-cell sequencing, are potential tools in identifying inflammatory signatures, miRNAs, and gene expression. Proteomic measures, including anti-C1q antibodies, cytokines, TLRs, VCAM-1, NGAL osteopontin, angiostatin, have been considered helpful to provide a more profound comprehension of the disease pathogenic processes. Metabolomic approaches may identify several abnormal metabolite profiles related to the impairment of cellular functions. Together, these accurate, non-invasive, and moderate-cost propedeutic resources may be the novel tools for recognizing, distinguishing, and predicting LN progression and prognosis. Furthermore, omics evaluation may also predict responsiveness to treatment and, consequently, change the way we manage LN cases in the near future.

Background: The MAO enzyme is presented in the brain and peripheral tissues and is a significant enzyme that is responsible for the deamination of biogenic amines and thus the regulation of neurotransmitter levels. The reaction of these neurotransmitters with the MAO enzyme produces aldehyde and free amine. MAO enzyme consists of two isoforms, MAO-A and MAO-B, which are characterized by amino acid sequence, three-dimensional structure, substrate preference, and inhibitor selectivity. Dopamine, tyramine, and tryptamine are substrates of both MAO isoforms and MAO inhibitors such as clorgiline and selegiline, which are used as medications in neurodegenerative and neurological diseases. In particular, MAO-A inhibitors are used in the treatment of depression, while MAO-B inhibitors are used in the treatment of Parkinson's disease. It is also investigated whether MAO-B inhibitors are effective in the treatment of Alzheimer's disease. Nowadays, life expectancy has increased, as a result, neurodegenerative diseases such as Parkinson's and Alzheimer's disease have started to occur more frequently. The elderly population is increasing day by day. As a result of these common diseases in elderly people, these people are unable to do their jobs and need care. Therefore, these diseases have become a significant health problem in society. Methods: In this study, review, inclusion, and exclusion criteria were used. Peer-reviewed research articles were searched. The quality of the examined articles was evaluated with standard tools. The information obtained was analyzed conceptually by using qualitative content analysis methodology. Results: One hundred and five papers were included in the review. The current MAO-B inhibitors and their usage areas are discussed together with the structures of the drugs; also, their possible effects in Alzheimer’s and Parkinson’s treatment are evaluated. In addition, different articles have been compiled in which structures such as arylalkylamines, chalcones, benzoquinone, benzoxazinone, and chromen are substituted with various functional groups and aromatic rings, along with thestructures of 44 different compounds that have recently been developed and their inhibitory effects on MAO-B enzyme. As a result, the structure required for MAO-B inhibition and SAR studies is discussed. Conclusion: Many studies demonstrate that MAO-B activity increases with age in brain tissue, cerebrospinal fluid (CSF), and platelets in Alzheimer's patients. This suggests that MAO-B inhibitor drugs, which may be effective in the treatment of Parkinson's disease, may also be effective in the treatment of Alzheimer's disease. This article was written to explain the multifaceted MAO-B inhibitor molecules.

The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non- ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD.

Background: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer’s disease. Due to the increasing number of Alzheimer’s patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. Objective: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer’s disease. Methods: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. Results: Synthesized aminoalkanamides were characterized as potent 5-HT1A receptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. Conclusion: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer’s disease.