Mini Reviews in Medicinal Chemistry - Volume 20, Issue 10, 2020

Pyrrole is a very important pharmacophoric moiety. It has been widely incorporated into the skeleton of antitumor, anti-inflammatory, antibacterial, antioxidant and antifungal active substances. Access to this key heterocycle by diverse routes is particularly attractive in terms of chemistry, and also from the environmental point of view. The present minireview summarizes the reported methods for the preparation of highly substituted pyrrole derivatives based on the one-pot multicomponent reaction of aldehydes, primary amines, and oxalacetate analogues as well as their biology.

Sepsis is still a severe health problem worldwide with high morbidity and mortality. Blood bacterial culture remains the gold standard for the detection of pathogenic bacteria in bloodstream infections, but it is time-consuming, and both the sophisticated equipment and well-trained personnel are required. Immunoassays and genetic diagnosis are expensive and limited to specificity and sensitivity. Aptamers are single-stranded deoxyribonucleic acid (ssDNA) and ribonucleic acid (RNA) oligonucleotide or peptide sequence generated in vitro based on the binding affinity of aptamer-target by a process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX). By taking several advantages over monoclonal antibodies and other conventional small-molecule therapeutics, such as high specificity and affinity, negligible batch-to-batch variation, flexible modification and production, thermal stability, low immunogenicity and lack of toxicity, aptamers are presently becoming promising novel diagnostic and therapeutic agents. This review describes the prospective application of aptamerbased laboratory diagnostic assays and therapeutics for pathogenic bacteria and toxins in bloodstream infections.

The α7 nicotinic acetylcholine receptor is a homopentameric ion-channel of the Cys-loop superfamily characterized by its low probability of opening, high calcium permeability, and rapid desensitization. The α7 receptor has been targeted for the treatment of the cognitive symptoms of schizophrenia, depression, and Alzheimer’s disease, but it is also involved in inflammatory modulation as a part of the cholinergic anti-inflammatory pathway. Despite its functional importance, in silico studies of the α7 receptor cannot produce a general model explaining the structural features of receptor activation, nor predict the mode of action for various ligand classes. Two particular problems in modeling the α7 nAChR are the absence of a high-resolution structure and the presence of five potentially nonequivalent orthosteric ligand binding sites. There is wide variability regarding the templates used for homology modeling, types of ligands investigated, simulation methods, and simulation times. However, a systematic survey focusing on the methodological similarities and differences in modeling α7 has not been done. In this work, we make a critical analysis of the modeling literature of α7 nAChR by comparing the findings of computational studies with each other and with experimental studies under the main topics of structural studies, ligand binding studies, and comparisons with other nAChR. In light of our findings, we also summarize current problems in the field and make suggestions for future studies concerning modeling of the α7 receptor.

Botulinum toxin is a neurotoxin produced by Clostridium botulinum and some other relative species. It causes a lethal disease called botulism. It can enter the body via infections by Clostridium (e.g. wound and children botulism) or by direct contact with the toxin or eating contaminated food (food-borne botulism). Botulinum toxin is also considered as a relevant biological warfare agent with an expected high number of causalities when misused for bioterrorist or military purposes. The current paper surveys the actual knowledge about botulinum toxin pathogenesis, the manifestation of poisoning, and current trends in diagnostics and therapeutics. Relevant and recent literature is summarized in this paper.

Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of Mitogen-Activated Protein Kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian Target of Rapamycin (mTOR). One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest the reduction of the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception. Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G Protein Coupled Receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations to post-receptor interactions through shared signal transduction pathways. This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.

Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

Inhibitors of monoamine oxidase (MAO) have shown therapeutic values in a variety of neurodegenerative diseases such as depression, Parkinson’s disease and Alzheimer’s disease. Heterocyclic compounds exhibit a broad spectrum of biological activities and vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel single heterocyclic derivatives with MAO inhibitory activities during the past decade. This review covers recent pharmacological advancements of single heterocyclic moiety along with structure- activity relationship to provide better correlation among different structures and their receptor interactions.

Tropical infectious diseases cause millions of deaths every year in developing countries, with about half of the world population living at risk. Mayaro virus (MAYV) is an emerging arbovirus that causes Mayaro fever, which is characterized by fever, headache, diarrhea, arthralgia, and rash. These symptoms can be clinically indistinguishable from other arboviruses, such as Dengue, Zika, and Chikungunya, which makes the diagnosis and treatment of the disease more difficult. Though, the Mayaro virus is a potential candidate to cause large-scale epidemics on the scale of ZIKV and CHIKV. Despite this, there is no licensed vaccine or antiviral for the treatment of Mayaro fever and most arboviruses, so the design and development of candidates for antiviral drugs are urgently needed. In this context, this mini-review aims to provide an overview of studies of anti-MAYV derivatives and highlight the importance of the discovery and development of promising drug candidates for Mayaro fever.

Background: Benzothiazine derivatives, because of their various biological activities have attracted particular attention in Med Chem and drug discovery efforts. The synthetic modifications of 1,2-benzothiazine 1,1-dioxides have been undertaken in order to explore and identify novel compounds or new analogues possessing promising biological activities. In our effort we have designed -oxicam derived bezothiazine-1,2,3-triazole derivatives as potential antibacterial agents. Methods: These compounds were synthesized via a multi-step sequence involving the Cu catalyzed azide- alkyne cycloaddition (CuAAC) as a key step. The CuAAC proceeded at room temperature in DMF to afford 26 novel molecules in good (70-90%) yields. Results: All these compounds were tested for their antibacterial properties against four strains of bacterial microorganisms and subsequently cytotoxic properties against lung and colon cancer cell lines. The compound 4e showed activities against majority of the bacterial species used (nearly comparable to amoxicillin, ciprofloxacin and ofloxacin against P. vulgaris) whereas 4d and 4f showed cytotoxicities selective towards cancer cells. Conclusion: The present bezothiazine-1,2,3-triazole framework represents a new template for the identification of novel and potent antibacterial/anticancer agents.