Current Medicinal Chemistry - Volume 28, Issue 15, 2021

COVID-19, a type of infection that emerged in Wuhan, has become a pandemic affecting people worldwide and is rapidly spreading and evolving. Day by day, the confirmed cases and deaths are increasing many folds. SARS-CoV-2 is a novel virus; therefore, limited data are available to curb the disease. Epidemiological approaches, such as isolation, quarantine, social distancing, lockdown, and curfew, are being employed to halt the spread of the disease. Individual and joint efforts all over the world are producing a wealth of data and information which are expected to produce therapeutic strategies against COVID-19. Current research focuses on the utilization of antiviral drugs, repurposing strategies, vaccine development, as well as basic to advanced research about the organism and the infection. The review focuses on its life cycle, targets, and possible therapeutic strategies, which can lead to further research and development of COVID-19 therapy.

Background: Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases. Methods: We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH’s COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value. Results: 291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 – 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens. Conclusion: The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.

Stress is a constant threat for homeostasis and is represented by different extrinsic and intrinsic stimuli (stressors, Hans Selye’s "noxious agents"), such as aggressive behavior, fear, diseases, physical activity, drugs, surgical injury, and environmental and physiological changes. Our organisms respond to stress by activating the adaptive stress system to activate compensatory responses for restoring homeostasis. Nerve Growth Factor (NGF) was discovered as a signaling molecule involved in survival, protection, differentiation, and proliferation of sympathetic and peripheral sensory neurons. NGF mediates stress with an important role in translating environmental stimuli into physiological and pathological feedbacks since NGF levels undergo important variations after exposure to stressful events. Psychological stress, lifestyle stress, and oxidative stress are well known to increase the risk of mental disorders such as schizophrenia, major depressive disorders, bipolar disorder, alcohol use disorders and metabolic disorders such as metabolic syndrome. This review reports recent works describing the activity of NGF in mental and metabolic disorders related to stress.

Paroxetine is a potent inhibitor of serotonin reuptake and is widely prescribed for the treatment of depression and other neurological disorders. The synthesis of paroxetine and the possibility to prepare derivatives with a specific substitution pattern that may allow their use as biological probes is an attractive topic especially for medicinal chemists engaged in neurosciences research. Considering the extensive work that was developed in the last decade on the total synthesis of paroxetine, this review summarizes the most important contributions in this field, organized according to the reagent that was used as a starting material. Most of the methods allowed to prepare paroxetine in 4-9 steps with an overall yield of 9-66%. Despite the progress made in this area, there is still room for improvement, searching for new eco-friendly and sustainable synthetic alternatives.

With the recent market approval of Pitolisant (Wakix®), the interest in clinical application for novel multifunctional histamine H3 receptor antagonists has clearly increased. Several combinations of different H3R pharmacophores with pharmacophoric elements of other G-protein coupled receptors, transporters, or enzymes have been synthesized by numerous pharmaceutical companies and academic institutions. Since central nervous system disorders are characterized by diverse physiological dysfunctions and deregulations of a complex network of signaling pathways, optimal multipotent drugs should simultaneously and peculiarly modulate selected groups of biological targets. Interestingly, very recent studies have shown that some clinically evaluated histamine H3 receptor antagonists possess a nanomolar affinity for sigma-1 receptor binding sites, suggesting that this property might play a role in their overall efficacy. The sigma-1 receptor, unusual and yet obscure protein, is supposed to be involved in numerous CNS pathologies through neuroprotection and neuroplasticity. These two different biological structures, histamine H3 and sigma-1 receptors, combined, can represent a potential fruitful target for therapeutic developments in tackling numerous human diseases.

Background: Botulinum toxin type A (BoNT-A) is widely employed for cosmetic purposes and in the treatment of certain diseases such as strabismus, hemifacial spasm and focal dystonia among others. BoNT-A effect mainly acts at the muscular level by inhibiting the release of acetylcholine at presynaptic levels consequently blocking the action potential in the neuromuscular junction. Despite the great progress in approval and pharmaceutical usage, improvement in displacing BoNT-A to other pathologies has remained very limited. Patients under diagnosis of several types of cancer experience pain in a myriad of ways; it can be experienced as hyperalgesia or allodynia, and the severity of the pain depends, to some degree, on the place where the tumor is located. Pain relief in patients diagnosed with cancer is not always optimal, and as the disease progresses, transition to more aggressive drugs, like opioids is sometimes unavoidable. In recent years BoNT-A employment in cancer has been explored, as well as an antinociceptive drug; experiments in neuropathic, inflammatory and acute pain have been carried out in animal models and humans. Although its mechanism has not been fully known, evidence has shown that BoNT-A inhibits the secretion of pain mediators (substance P, Glutamate, and calcitonin gene related protein) from the nerve endings and dorsal root ganglion, impacting directly on the nociceptive transmission through the anterolateral and trigeminothalamic systems. Aim: The study aimed to collect available literature regarding molecular, physiological and neurobiological evidence of BoNT-A in cancer patients suffering from acute, neuropathic and inflammatory pain in order to identify possible mechanisms of action in which the BoNT-A could impact positively in pain treatment. Conclusion: BoNT-A could be an important neo-adjuvant and coadjuvant in the treatment of several types of cancer, to diminish pro-tumor activity and secondary pain.

Malaria remains a serious problem in global public health, particularly widespread in South America and in tropical regions of Africa and Asia. Chemotherapy is actually the only way to treat this poverty-related disease, since an effective vaccine is not currently available. However, the onset of resistance to the most common antimalarial drugs sometimes makes the current therapeutic regimen problematic. Therefore, the identification of new targets for a new drug discovery process is an urgent priority. In this context, falcipain-2 and falcipain- 3 of P. falciparum represent the key enzymes in the life-cycle of the parasite. Both falcipain- 2 and falcipain-3 are involved in hemoglobin hydrolysis, an essential pathway to provide free amino acids for the parasite metabolic needs. In addition, falcipain-2 is involved in cleaving ankirin and band 4.1 protein, which are cytoskeletal elements essential for the stability of the red cell membrane. This review article is focused on the most recent and effective inhibitors of falcipain-2 and falcipain-3, with particular attention to peptide, peptidomimetic or nonpeptide inhibitors, which targeted one or both the malarial cysteine proteases, endowed with a consistent activity against P. falciparum.

Background: Periodontitis is an immune-inflammatory disease that leads to the progressive destruction of bone and connective tissue in the periodontal area. The cytokine network plays a primary role in tissue homeostasis, the recruitment of immune cells to control the pathogenic impact and the regulation of osteoclastic function, thus modulating the intensity and duration of the immune response. This review provides an update on the main cytokines implicated in the pathogenesis and progression of periodontitis and their targeting potential in order to enrich current treatment options. Methods: A structured search of bibliographic databases (PubMed, MEDLINE, Scopus) was performed for peer-reviewed cytokine studies focused on periodontitis the last ten years. A qualitative content analysis was performed in screened papers and a critical discussion of main findings is provided. Results: An altered cytokine profile has been detected in periodontitis patients and the interplay of pro-inflammatory and/or anti-inflammatory cytokines has been associated with disease pathogenesis. Among the most prominent pro-inflammatory cytokines, TNF-α, IL-1β, IL-17, IL-6 and the chemokines CXCL-6, CXCL-8 are overexpressed in periodontitis patients and correlate with disease progression. On the other hand, the anti-inflammatory IL-4 and IL- 11 levels are reduced while IL-12 and IFN-γ expression play a dual role in periodontal disease. Current periodontitis treatment strategies include selective antibiotics, antimicrobial photodynamic therapy and probiotics, which can modulate the cytokine network and when applied in combination with specific anti-cytokine agents can exert additional beneficial effects. Conclusion: It is evident that cytokines play a central regulatory role in the inflammatory process and immune cell response that underlies bone destruction in periodontitis. Specific cytokine targeting should be considered as a complementary therapeutic scheme to current periodontal management.