Current Medicinal Chemistry - Volume 28, Issue 24, 2021

At present, a pandemic of antibiotic-resistant infectious diseases is an evergrowing threat. The need for new antibiotics and ways to combat antibiotic resistance is glaring. This review will focus on two different privileged scaffolds, the indole and the indoline, as useful nuclei for novel antibacterial compounds. The indole, a moiety found in numerous approved drugs for many disease states, has recently been studied for its usefulness as a scaffold for compounds that have activity against antibiotic-resistant bacteria, especially against methicillin-resistant Staphylococcus aureus (MRSA). The indoline is a scaffold with significantly less historical studies and FDA-approved drugs and it has attracted new interest in drug design and development. In recent years, indoline-containing compounds have been shown to have antibacterial activity as well as activity as a resistance- modifying agent (RMA), which act to improve the effectiveness of current antibiotic therapies that have known resistance.

Prostate cancer is the fifth cause of tumor-related deaths in man worldwide. Due to its long latency period, this pathology represents an ideal type of disease for chemopreventive studies. Among the drugs considered thus far for the treatment of prostate cancer, the natural compound resveratrol emerged as very promising. Resveratrol is widely recognized as a chemopreventive agent and was shown to potentiate the antitumor activity of conventional chemotherapeutics in several tumors, including prostate cancer. Here, we overview the literature of the last five years and summarize the recent achievements of resveratrol and its derivatives as antimetastatic agents in prostate cancer. Moreover, drug combination studies as well as nanomedicine approaches proposed to improve resveratrol activity and to overcome delivery drawbacks are addressed. The last part of the review discusses the clinical trials containing resveratrol ongoing on cancer patients.

Background: In recent years much research has been devoted to the deployment of biomarkers in the field of heart failure. Objectives: To study the potential of post-transcriptional regulation by microRNAs on the diagnosis, management and therapy of heart failure. Methods: Literature search focuses on the role of microRNAs in heart failure. Results: MicroRNAs are expressed and regulated in the course of the pathological manifestations of heart failure (HF). This wide and uncharted area of genetic imprints consisting of small non-coding RNA molecule is upregulated and released into the bloodstream from organs under certain conditions and or stress. The use of genetically based strategies for the management of HF has gained great interest in the field of biomedical science because they can be used as biomarkers providing information regarding cardiac status and function. They also appear as promising tools with therapeutic potential because of their ability to induce changes at the cellular level without creating alterations in the gene sequence. In addition, with the advances in genomic sequencing, quantification and synthesis in technologies of microRNAs identification as well as the growing knowledge of the biology of miRNAs and their involvement in HF, it is expected to favorably affect the prognosis of HF patients. Conclusion: MicroRNAs are involved in the regulation of multibiological processes involved in the progress of heart failure. More studies are needed to achieve a clinical valuable implementation of microRNAs in the management of HF.

The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.

The PROTAC (PROteolysis TArgeting Chimera) technology is a target protein degradation strategy, based on the ubiquitin-proteasome system, which has been gradually developed into a potential means of targeted cancer therapy in recent years. This strategy has already shown significant advantages over traditional small-molecule inhibitors in terms of pharmacodynamics, selectivity, and drug resistance. Several small molecule PROTACs have been in Phase I clinical trial. Herein, we have introduced the mechanism, characteristics, and advantages of PROTAC strategy. And we have summarized the recent advances in the development of small-molecule PROTACs for cancer treatment. We hope this review will be helpful in optimizing the design of the ideal small- molecule PROTACs and advancing targeted anticancer research.

HIV-1 integrase catalyzed the insertion of viral DNA into the genome of human cells in the process of retrotranscription. Integrase is an attractive target for HIV-1 treatment due to the lack of its homologue in human cells and its vital role in HIV-1 replication. Although major progress in the development of HIV-1 integrase inhibitors has been made, some thorny problems, such as drug resistance, led to the further study of HIV-1 integrase inhibitors. This review briefly discussed the structure, function, and mechanism of catalysis of HIV-1 integrase and made a different conclusion for recent advances in small-molecule inhibitors of HIV-1 integrase.

The development of biodegradable nanoparticles is an important tool for the biological transport of chemical compounds. The nanoencapsulation reduces the biopharmaceutical and pharmacokinetic drawbacks of compounds and enhances their biological properties. Naturally occurring polymers such as proteins and polysaccharides have been widely applied in the development of nanostructured systems of several therapeutic agents. Among them is chitosan, a crustacean-carapace-chitin derived biopolymer. In addition to its biocompatibility and biodegradability, chitosan is known for its mucoadhesion properties. Chitosan-based nanostructured systems potentiate most of the aspects of the loaded drugs, including cellular transport and other biological effects. The use of chitosan nanoparticles enhances permeation, stability, and bioactivity of natural compounds. In this review, an overview of the main features of chitosan nanoparticles that improved in vitro and in vivo effects of bioactive natural molecules is given, emphasizing the results obtained with curcumin.

Background: Electrostatic interactions are one of the forces guiding the binding of molecules to proteins. The assessment of this interaction through computational approaches makes it possible to evaluate the energy of protein-drug complexes. Objective: Our purpose here is to review some of the methods used to calculate the electrostatic energy of protein-drug complexes and explore the capacity of these approaches for the generation of new computational tools for drug discovery using the abstraction of scoring function space. Methods: Here, we present an overview of the AutoDock4 semi-empirical scoring function used to calculate binding affinity for protein-drug complexes. We focus our attention on electrostatic interactions and how to explore recently published results to increase the predictive performance of the computational models to estimate the energetics of protein- drug interactions. Public data available at Binding MOAD, BindingDB, and PDBbind were used to review the predictive performance of different approaches to predict binding affinity. Results: A comprehensive outline of the scoring function used to evaluate potential energy available in docking programs is presented. Recent developments of computational models to predict protein-drug energetics were able to create targeted-scoring functions to predict binding to these proteins. These targeted models outperform classical scoring functions and highlight the importance of electrostatic interactions in the definition of the binding. Conclusion: Here, we reviewed the development of scoring functions to predict binding affinity through the application of a semi-empirical free energy scoring function. Our studies show the superior predictive performance of machine learning models when compared with classical scoring functions and the importance of electrostatic interactions for binding affinity.

Inflammasome research has primarily focused on neurological tissue, particularly on damaged tissue. Most current neurological literature involves in vivo and in vitro studies utilizing astroglia, as astroglia express the cytoskeletal glial fibrillary acidic protein (GFAP), which is used as a hallmark of neuropathological disorders. Research suggests that astrocytes respond to all forms of neurological damage or disease through reactive astrogliosis. Additionally, there is a consensus among scientists that inflammasomes play an important role in neuroinflammation. This review focuses on the latest developments in inflammasome biology, describing the current understanding of how inflammasomes can be triggered in the brain and summarizing the literature on the relevance of inflammasome NLR in prevalent neurological diseases.

Background: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low μM concentrations. Objective: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. Methods: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. Results: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti–influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 μM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. Conclusion: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.

Background: Nucleopeptides are chimeric compounds of biomedical importance carrying DNA nucleobases anchored to peptide backbones with the ascertained capacity to bind nucleic acids. However, their ability to interact with proteins involved in pathologies of social relevance is a feature that still requires investigation. The worrying situation currently observed worldwide for the COVID-19 pandemic urgently requires the research on novel anti-SARSCoV- 2 molecular weapons, whose discovery can be aided by in silico predictive studies. Objective: The aim of this work is to explore by spectroscopic methods novel features of a thymine-bearing nucleopeptide based on L-diaminopropanoic acid, including conformational aspects as well as its ability to bind proteins, starting from bovine serum albumin (BSA) as a model protein. Moreover, in consideration of the importance of targeting viral proteins in the current fight against COVID-19, we evaluated in silico the interaction of the nucleopeptide with some of the most relevant coronavirus protein targets. Methods: First, we investigated via circular dichroism (CD) the conformational behaviour of this thymine-bearing nucleopeptide with temperature: we observed CD spectral changes, particularly passing from 15 to 35 °C. Scanning Electron Microscopy (SEM) analysis of the nucleopeptide was also conducted on nucleopeptide solid samples. Additionally, CD binding and preliminary in silico investigations were performed with BSA as a model protein. Moreover, molecular dockings were run using as targets some of the main SARS-CoV-2 proteins. Results: The temperature-dependent CD behaviour reflected the three-dimensional rearrangement of the nucleopeptide at different temperatures, with higher exposure to the solvent of its chromophores at higher temperatures compared to a more stacked structure at a low temperature. SEM analysis of nucleopeptide samples in the solid-state showed a granular morphology, with a low roughness and some thread structures. Moreover, we found through spectroscopic studies that the modified peptide bound the albumin target by inducing significant changes to the protein secondary structure. Conclusion: CD and preliminary in silico studies suggested that the nucleopeptide bound the BSA protein with high affinity according to different binding modes, as testified by binding energy scores lower than -11 kcal/mol. Interestingly, a predictive study performed on 3CLpro and other SARS-CoV-2 protein targets suggested the potential ability of the nucleopeptide to bind with good affinity the main protease of the virus and other relevant targets, including the RNAdependent RNA polymerase, especially when complexed with RNA, the papain-like protease, and the coronavirus helicase at the nucleic acid binding site.

Background: Methotrexate (MTX) is the representative drug among the disease- modifying anti-rheumatic drugs. However, the conventional treatment with MTX showed many limitations and side effects. Objective: To strengthen the targeting ability and circulation time of MTX in the treatment of rheumatoid arthritis, the present study focused on developing a novel drug delivery system of methotrexate-loaded human serum albumin nanoparticles (MTX-NPs) modified by mannose, which are referred to as MTX-M-NPs. Methods: Firstly, mannose-derived carboxylic acid was synthesized and further modified on the surface of MTX-NPs to prepare MTX-M-NPs. The formulation of nanoparticles was optimized by the method of central composite design (CCD), with the drug lipid ratio, oil-aqueous ratio, and cholesterol or lecithin weight as the independent variables. The average particle size and encapsulation efficiency were the response variables. The response of different formulations was calculated, and the response surface diagram, contour diagram, and mathematical equation were used to relate the dependent and independent variables to predict the optimal formula ratio. The uptake of MTX-M-NPs by neutrophils was studied through confocal laser detection. Further, MTX-M-NPs were subjected to assessment of the pharmacokinetics profile after intravenous injection with Sprague-Dawley rats. Results: This targeting drug delivery system was successfully developed. Results from Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy analysis can verify the successful preparation of this drug delivery system. Based on the optimized formula, MTX-M-NPs were prepared with a particle size of 188.17 ± 1.71 nm and an encapsulation rate of 95.55 ± 0.33%. MTX-M-NPs displayed significantly higher cellular uptake than MTX-NPs. The pharmacokinetic results showed that MTX-M-NPs could prolong the in vivo circulation time of MTX. Conclusion: This targeting drug delivery system laid a promising foundation for the treatment of RA.