Current Medicinal Chemistry - Volume 31, Issue 7, 2024

Elacestrant was approved by the US FDA on January 27, 2023, for treating postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2- negative, ESR1-mutated advanced or metastatic breast cancer with disease progression prior to using at least one line of endocrine therapy. In this short perspective, physicochemical properties, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interaction, and treatment-related adverse reactions of elacestrant are summarized.

Background: Dihydrofolate reductase (DHFR) is an indispensable enzyme required for the survival of most prokaryotic and eukaryotic cells as it is involved in the biosynthesis of essential cellular components. DHFR has attracted a lot of attention as a molecular target for various diseases like cancer, bacterial infection, malaria, tuberculosis, dental caries, trypanosomiasis, leishmaniasis, fungal infection, influenza, Buruli ulcer, and respiratory illness. Various teams of researchers have reported different DHFR inhibitors to explore their therapeutic efficacy. Despite all the progress made, there is a strong need to find more novel leading structures, which may be used as better and safe DHFR inhibitors, especially against the microorganisms which are resistant to the developed drug candidates. Objective: This review aims to pay attention to recent development, particularly made in the past two decades and published in this field, and pay particular attention to promising DHFR inhibitors. Hence, an attempt has been made in this article to highlight the structure of dihydrofolate reductase, the mechanism of action of DHFR inhibitors, most recently reported DHFR inhibitors, diverse pharmacological applications of DHFR inhibitors, reported in silico study data and recent patents based on DHFR inhibitors to comprehensively portray the current scenery for researchers interested in designing novel DHFR inhibitors. Conclusion: A critical review of recent studies revealed that most novel DHFR inhibitor compounds either synthetically or naturally derived are characterized by the presence of heterocyclic moieties in their structure. Non-classical antifolates like trimethoprim, pyrimethamine, and proguanil are considered excellent templates to design novel DHFR inhibitors, and most of them have substituted 2,4-diamino pyrimidine motifs. Targeting DHFR has massive potential to be investigated for newer therapeutic possibilities to treat various diseases of clinical importance.

According to the World Health Organization (WHO), cancer is the second cause of death worldwide, responsible for almost 10 million deaths and accounting for one in every six deaths. It is a disease that can affect any organ or tissue with rapid progression to the final stage, which is metastasis, in which the disease spreads to different regions of the body. Many studies have been carried out to find a cure for cancer. Early diagnosis contributes to the individual achieving the cure; however, deaths are increasing considerably due to late diagnosis. Thus, this bibliographical review discussed several scientific research works pointing to in silico analyses in the proposition of new antineoplastic agents for glioblastoma, breast, colon, prostate, and lung cancer, as well as some of their respective molecular receptors involved in molecular docking simulations and molecular dynamics. This review involved articles describing the contribution of computational techniques for the development of new drugs or already existing drugs with biological activity; thus, important data were highlighted in each study, such as the techniques used, results obtained in each study, and the conclusion. Furthermore, 3D chemical structures of the molecules with the best computational response and significant interactions between the tested molecules and the PDB receptors were also presented. With this, it is expected to help new research in the fight against cancer, the creation of new antitumor drugs, and the advancement of the pharmaceutical industry and scientific knowledge about studied tumors.

Cancer, the second leading cause of death worldwide, is a major health problem. Chemotherapy, radiation therapy and surgery are current treatments for cancer. Most anticancer drugs have severe toxic effects and are required to be administered in cycles to reduce toxicity and prevent resistance. Plant-based drugs have shown a potential for treatment of cancer, and various plant secondary metabolites have shown promising antitumor activity against several cancer cell lines, such as leukemia, colon cancer, prostate cancer, breast cancer and lung cancer. Vincristine, etoposide, topotecan and paclitaxel, which are of natural origin, are successfully used in clinical practice, and this has generated interest in natural compounds as anticancer agents. Some phytoconstituents like curcumin, piperine, allicin, quercetin and resveratrol have been extensively researched and reviewed. In the current study, we have reviewed several plants like Athyrium hohenackerianum, Aristolochia baetica, Boswellia serrata, Panax ginseng, Berberis vulgaris, Tanacetum parthenium, Glycine max, Combretum fragrans, Persea americana, Raphanus sativus, Camellia sinensis, and Nigella sativa for their source, key phytoconstituents, and anticancer activity along with their toxicity profile. Few phytoconstituents like boswellic acid, sulforaphane and ginsenoside showed excellent anticancer activity compared to standard drugs and are potential clinical candidates.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/- functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin- based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

Background: Zingiber officinale Roscoe (Ginger) belongs to the Zingiberaceae family, which is renowned for its rich nutritional and phytochemical composition, and has been validated for its anti-diabetic and anti-inflammatory properties via in vitro, in vivo, and clinical studies. Nonetheless, a comprehensive review of these pharmacological studies, especially clinical studies, together with an analysis of the mechanism of action of the bioactive compounds is still lacking. This review provided a comprehensive and updated analysis of the anti-diabetic efficacy of Z. officinale and its compounds ginger enone, gingerol, paradol, shogaol, and zingerone. Methods: The present systematic review was conducted using the PRISMA guidelines. Scopus, ScienceDirect, Google Scholar, and PubMed were the main databases used for retrieving information from inception to March 2022. Results: From the findings obtained, Z. officinale can be regarded as a therapeutic species showing significant improvement in clinical studies on glycemic parameters (Fasting blood glucose (FBG), hemoglobin A1C (HbA1c), and insulin resistance). In addition, the bioactive compounds of Z. officinale act via several mechanisms as revealed by in vitro and in vivo studies. Overall, these mechanisms were by increasing glucose-stimulated insulin secretion, sensitising insulin receptors and raising glucose uptake, translocation of GLUT4, inhibition of advanced glycation end product-induced increase of reactive oxygen species, regulation of hepatic gene expression of enzymes associated with glucose metabolism, regulation of the level of pro-inflammatory cytokines, amelioration of the pathological injuries of kidneys, protective effect on the morphology of β-cells as well as its antioxidant mechanisms, among others. Conclusion: Z. officinale and its bioactive compounds displayed promising results in in vitro and in vivo systems, nevertheless, it is highly recommended that human trials be conducted on these compounds since clinical studies are the core of medical research and considered the final stages of the drug development process.

The fibrosis of tissues and organs occurs via an aberrant tissue remodeling process characterized by an excessive deposition of extracellular matrix, which can lead to organ dysfunction, organ failure, and death. Because the pathogenesis of fibrosis remains unclear and elusive, there is currently no medication to reverse it; hence, this process deserves further study. Activating protein-1 (AP-1)-comprising Jun (c-Jun, JunB, JunD), Fos (c-fos, FosB, Fra1, and Fra2), and activating transcription factor-is a versatile dimeric transcription factor. Numerous studies have demonstrated that AP-1 plays a crucial role in advancing tissue and organ fibrosis via induction of the expression of fibrotic molecules and activating fibroblasts. This review focuses on the role of AP-1 in a range of fibrotic disorders as well as on the antifibrotic effects of AP-1 inhibitors. It also discusses the potential of AP-1 as a new therapeutic target in conditions involving tissue and organ fibrosis.