Current Medicinal Chemistry - Volume 29, Issue 32, 2022

The discovery of a new drug requires over a billion dollars and around 12 years of research efforts, and toxicity is the leading reason for the failure to approve candidate drugs. Many alternative methods have been validated to detect toxicity as early as possible to diminish the waste of resources and efforts in medicinal chemistry research, and in vivo alternative methods are especially valuable for the amount of information they can provide at little cost and in a short time. In this work, we present a review of the literature published between the years 2000 and 2021 on in vivo alternative methods of toxicity screening employed in medicinal chemistry, which we believe will be useful because, in addition to shortening the research time, these studies provide much additional information aside from the toxicity of drug candidate compounds. These in vivo models include zebrafish, Artemia salina, Galleria mellonella, Drosophila melanogaster, planarians, and Caenorhabditis elegans. The most published ones in the last decade were zebrafish, D. melanogaster, and C. elegans due to their reliability, ease, and cost-effectiveness in implementation and flexibility. Special attention is given to C. elegans because of its rising popularity, a wide range of uses, including toxicity screening, and active effects measurement, from antioxidant effects to anthelmintic and antimicrobial activities, and its fast and reliable results. Over time, C. elegans also became a viable high-throughput (HTS) automated drug screening option. Additionally, this manuscript lists briefly the other screening methods used for the initial toxicological analyses and the role of alternative in vivo methods in these scenarios, classifying them as in silico, in vitro and alternative in vivo models that have been receiving a growing increase in interest in recent years.

Dementia and frailty increase health adversities in older adults, which are topics of growing research interest. Frailty is considered to correspond to a biological syndrome associated with age. Frail patients may ultimately develop multiple dysfunctions across several systems, including stroke, transient ischemic attack, vascular dementia, Parkinson's disease, Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, cortico-basal degeneration, multiple system atrophy, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Patients with dementia and frailty often develop malnutrition and weight loss. Rigorous nutritional, pharmacological, and non-pharmacological interventions generally are required for these patients, which is a challenging issue for healthcare providers. A healthy diet and lifestyle instigated at an early age can reduce the risk of frailty and dementia. For optimal treatment, accurate diagnosis involving clinical evaluation, cognitive screening, essential laboratory evaluation, structural imaging, functional neuroimaging, and neuropsychological testing is necessary. Diagnosis procedures best apply the clinical diagnosis, identifying the cause(s) and the condition(s) appropriate for treatment. The patient's history, caregiver's interview, physical examination, cognitive evaluation, laboratory tests, and structural imaging should best be involved in the diagnostic process. Varying types of physical exercise can aid the treatment of these disorders. Nutrition maintenance is a particularly significant factor, such as exceptionally high-calorie dietary supplements and a Mediterranean diet to support weight gain. The core purpose of this article is to investigate trends in the management of dementia and frailty, focusing on improving diagnosis and treatment. Substantial evidence builds the consensus that a combination of balanced nutrition and good physical activity is an integral part of treatment. Notably, more evidence-based medicine knowledge is required.

Adult hippocampal neurogenesis is a multistage mechanism that continues throughout the lifespan of human and non-human mammals. These adult-born neurons in the central nervous system (CNS) play a significant role in various hippocampus-dependent processes, including learning, mood regulation, pattern recognition, etc. Reduction of adult hippocampal neurogenesis, caused by multiple factors such as neurological disorders and aging, would impair neuronal proliferation and differentiation and result in memory loss. Accumulating studies have indicated that functional neuron impairment could be restored by promoting adult hippocampal neurogenesis. In this review, we summarized the small molecules that could efficiently promote the process of adult neurogenesis, particularly the agents that have the capacity of crossing the blood-brain barrier (BBB), and showed in vivo efficacy in mammalian brains. This may pave the way for the rational design of drugs to treat human neurodegenerative disorders in the future.

The incidence rate of opportunistic secondary infections through invasive fungi has been observed to be 14.5% to 27% in the SARS CoV pandemic during the year 2003. However, the incidence of SARS CoV-2 is accompanied by a substantial rise in secondary opportunistic infections like mucormycosis (black fungus), mainly in the immunocompromised individuals and diabetic patients taking steroids. Substantial rates of COVID-19 cases with mucormycosis were reported in India and other parts of the world. Previous research reports delineated the ability of Mucorales to invade the various tissues like lungs, brain, and sinus through the GRP78, and subsequently, this infection could invoke crusting, edema, and necrosis of the brain parenchyma, ptosis, proptosis, and vision loss due to intraorbital and intracranial complications. Similarities of these pathophysiological complications with already existing diseases are causing clinicians to face several challenges in order to diagnose and treat this disease effectively at the early stage. This minireview depicts the mucormycosis-induced immune and pathophysiological alterations in COVID-19 patients comorbid with diabetes and immunosuppression and also reported the various clinical manifestations, the therapeutic modalities, and the failures of anti-fungal vaccines. Therefore, the emerging mucormycosis in COVID-19 patients needs rapid investigation and selective optimization of the effective therapeutic modalities, including antifungal vaccines, to minimize the mortality rate.

Background: In a scenario of increased pathogens with multidrug resistance phenotypes, it is necessary to seek new pharmacological options. This fact is responsible for an increase in neoplasms and multiresistant parasitic diseases. In turn, snake venom- derived peptides exhibited cytotoxic action on fungal and bacterial strains, possibly presenting activities in resistant tumor cells and parasites. Therefore, the aim of this work is to verify an antitumor and antiparasitic activity of antimicrobial peptides derived from snake venom. Methods: For this purpose, searches were performed in the Pubmed, Embase and Virtual Health Library databases by combining the descriptors peptides, venom and snake with antitumor/ antiparasitic agent and in silico. The inclusion criteria: in vitro and in vivo experimental articles in addition to in silico studies. The exclusion criteria: articles that were out of scope, review articles, abstracts, and letters to the reader. Data extracted: peptide name, peptide sequence, semi-maximal inhibitory concentration, snake species, tumor lineage or parasitic strain, cytotoxicity, in vitro and in vivo activity. Results: In total 164 articles were found, of which 14 were used. A total of ten peptides with antiproliferative activity on tumor cells were identified. Among the articles, seven peptides addressed the antiparasitic activity. Conclusion: In conclusion, snake venom-derived peptides can be considered as potential pharmacological options for parasites and tumors, however more studies are needed to prove their specific activity.