Mini Reviews in Medicinal Chemistry - Volume 20, Issue 18, 2020

Fatty acid synthase (FASN) is a multifunctional enzyme involved in the production of fatty acids for lipid biosynthesis. FASN is overexpressed in multiple diseases like cancer, viral, nonalcoholic fatty liver disease, and metabolic disorders, making it an attractive target for new drug discovery for these diseases. In cancer, FASN affects the structure and function of the cellular membrane by channelizing with signaling pathways along with the post-translational palmitoylation of proteins. There are several natural and synthetic FASN inhibitors reported in the literature, a few examples are GSK 2194069 (7.7 nM), imidazopyridine (16 nM), epigallocatechin-3-gallate (42.0 μg/ml) and platensimycin (300 nM) but except for TVB-2640, none of the aforementioned inhibitors have made into clinical trials. The present review summarizes the recent advancements made in anticancer drug discovery targeting FASN. Furthermore, the review also provides insights into the medicinal chemistry of small molecule inhibitors targeting different FASN enzyme domains, and also critically analyzes the structural requirements for FASN inhibition with an objective to support rational design and development of new generation FASN inhibitors with clinical potential in diseases like cancer.

Coumarin belongs to a class of lactones that are fundamentally comprised of a benzene ring fused to an α-pyrone ring; these lactones are known as benzopyrones. Similarly, coumarin has a conjugated electron-rich framework and good charge-transport properties. Plants produce coumarin as a chemical response to protect themselves from predation. Coumarins are used in different products, such as cosmetics, additives, perfumes, aroma enhancers in various tobaccos and some alcoholic drinks, and they play a relevant role in natural products and in organic and medicinal chemistry. In addition, as candidate drugs, many coumarin compounds have strong pharmacological activity, low toxicity, high bioavailability and better curative effects and have been used to treat various types of diseases. Various endeavors were made to create coumarin-based anticoagulant, antimicrobial, antioxidant, anticancer, antidiabetic, antineurodegenerative, analgesic and anti-inflammatory agents. A class of chemical compounds called furocoumarins has phototoxic properties and is naturally synthesized via the fusion of coumarin to a furan ring in different plant species. Psoralens belong to the furocoumarin class and occur naturally in various plants, e.g., lemons, limes, and parsnips. Angelicin is an isomer of psoralens, and most furocoumarins, e.g., xanthotoxin, bergapten, and nodekenetin, are derivatives of psoralens or angelicin. The present work demonstrated that psoralen molecules exhibit anti-tumoral activity against breast cancer and influence different intracellular signals to maintain the high survival of breast cancer cells. Psoralens perform different functions, e.g., antagonize metabolic pathways, protease enzymes, and cell cycle progression and even interfere in the crosslinking between receptors and growth factor mitogenic signaling.

Piperonal, an important aromatic aldehyde containing the benzene ring fused to 1, 3- dioxolane moiety, widely occurred in nature and known for its fragrance similar to vanillin and cherry. Alterations in its structural features led to the access of a wide range of piperonal derivatives viz. pyrazolines, chalcones, benzothiazepines, benzoxazoles, triazoles etc. having remarkable pharmacological properties like antimicrobial, anticancer, antidiabetic, antitubercular activities, etc. Therefore, the present study has been designed to highlight the progress made in the area of piperonal and its derivatives till date with respect to their synthesis and pharmacological activities. This may facilitate the synthesis of more novel derivatives with improved biological activities. Various search engines like google, Pubmed, Scopus etc. were used to gather the related information using different keywords.

Uric acid is the end product of purine metabolism in humans. High uric acid levels form sodium urate crystals that trigger biological processes, which lead to the development of several diseases, including diabetes, hyperuricemia, gout, inflammatory disease, kidney disease, cardiovascular disease and hypertension. Catechins have been suggested to be beneficial for the regulation of uric acid metabolic disorders due to their powerful antioxidant and anti-inflammatory properties. To identify an effective and safe natural substance that can decrease levels of serum uric acid to improve uric acid metabolism disorders. A search was performed on PubMed, Web of Science and Google Scholar to identify comprehensive studies that presented summarized data on the use of catechins in lowering uric acid levels in diseases. This review details the role of catechins in inhibiting the activity of xanthine oxidase to decrease uric acid overproduction in the liver and in regulating expressions of uric acid transporters, URAT1, OAT1, OAT3, ABCG2 and GLUT9, to balance levels of uric acid secretion and reabsorption through the kidney and intestine. Additionally, Catechins were also found to prevent monosodium urate-induced inflammatory reactions. In vivo, catechins can be used to decrease high uric acid levels that result from hyperuricemia and related diseases. Catechins can be used to maintain the balance of uric acid metabolism.

Wound healing is a multi-stage process during which a cascade of molecular and cellular events collaborate to restore the damaged tissue to its healthy state. The inability of the available therapies to effectively heal the wounds has imposed major problems on healthcare systems. Therefore, developing novel therapeutic modalities capable of enhancing wound healing process with no/or limited scar formation is of more importance. Different studies have investigated the potential of phytochemicals on the wound healing process. They have shown to exert anti-inflammatory, antioxidant, and antibacterial activities as well as promoting collagen synthesis and deposition, leading to enhancing wound healing. Nanotechnology, as an applicable knowledge, has provided versatile means to improve the efficiency and effectiveness of wound treatment. The application of nanoparticles has conferred various advantages in the field of wound treatment. They protect the therapeutics from degradation, release the cargo in a controlled fashion, possess healing properties, and can act as extracellular matrix (ECM) mimic. In this review, we discuss the naturally-occurring compounds with wound healing properties and their nano-formulation for skin wound therapy.

Glioblastoma multiforme (GBM) continues as one of the most lethal cerebral cancers despite standard therapeutic modalities, such as maximum surgical resection and chemoradiation. The minimal effectiveness of existing therapies necessitates the development of additional drug candidates that could improve the prognosis of GBM patients. Accumulating evidence suggests that calcium (Ca²⁺) is involved in the processes of cell proliferation, metastasis, angiogenesis, migration, and invasiveness. Therefore, Ca²⁺ could serve as a crucial regulator of tumorigenesis and a potential treatment target in GBM. In this context, specific natural products are known to modulate Ca²⁺ signaling pathways implicated in tumor growth, apoptosis, angiogenesis, and development of GBM. Here, the focus is on the function of Ca²⁺ as a therapeutic target in GBM and reviewing certain natural products that affect the signaling pathways of Ca²⁺.

The global spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes COVID-19 has become a source of grave medical and socioeconomic concern to human society. Since its first appearance in the Wuhan region of China in December 2019, the most effective measures of managing the spread of SARS-CoV-2 infection have been social distancing and lockdown of human activity; the level of which has not been seen in our generations. Effective control of the viral infection and COVID-19 will ultimately depend on the development of either a vaccine or therapeutic agents. This article highlights the progresses made so far in these strategies by assessing key targets associated with the viral replication cycle. The key viral proteins and enzymes that could be targeted by new and repurposed drugs are discussed.

The need for new therapeutics and drug delivery systems has become necessary owing to the public health concern associated with the emergence of multidrug-resistant microorganisms. Among the newly discovered therapeutic agents is cefiderocol, which was discovered by Shionogi Company, Japan as an injectable siderophore cephalosporin. Just like the other β-lactam antibiotics, cefiderocol exhibits antibacterial activity via cell wall synthesis inhibition, especially in Gram negative bacteria (GNB); it binds to the penicillin-binding proteins, but its unique attribute is that it crosses the periplasmic space of bacteria owing to its siderophore-like attribute; it also resists the activity of β-lactamases. Among all the synthesized compounds with the modified C-7 side chain, cefiderocol (3) presented the best and well-balanced activity against multi-drug resistant (MDR) Gram negative bacteria, including those that are resistant to carbapenem. İn this article, an overview of the recent studies on cefiderocol was presented.

The Zika virus (ZIKV) infection is a major public health concern in Brazil and worldwide, being a rapidly spreading disease with possible severe complications for pregnant women and neonates. There is currently no preventative therapy or specific treatment available. Within this context, drug repositioning is a very promising approach for the discovery of new treatment compounds, since old drugs may become new ones. Therefore, this paper aims to perform a literature mini-review to identify promising compounds to combat this virus. The mechanism of action at the molecular level and the structure-activity relationship of prototypes are discussed. Among the candidates identified, we highlight sofosbuvir, chloroquine and suramin, which present a greater quantity of experimental data to draw on for our discussion. The current treatment is palliative; therefore, this study is of paramount importance in identifying drug candidates useful for combating ZIKV.

Background and Objective: Due to the well-documented anti-proliferative activity of 2-thiohydantoin incorporated with pyrazole, oxadiazole, quinazoline, urea, β-naphthyl carbamate and Schiff bases, they are noteworthy in pharmaceutical chemistry. Methods: An efficient approach for the synthesis of a novel series of 2-thiohydantoin derivatives incorporated with pyrazole and oxadiazole has proceeded via the reaction of the acyl hydrazide with chalcones and/or triethyl orthoformate. Schiff bases were synthesized by the reaction of the acyl hydrazide with different aromatic aldehydes. Moreover, Curtius rearrangement was applied to the acyl azide to obtain the urea derivative, quinazoline derivative, and carbamate derivative. Results: The synthesized compounds structures were discussed and confirmed depending on their spectral data. The anticancer activity of these heterocyclic compounds was evaluated against the breast cancer cell line (MCF-7), where they showed variable activity. Compound 5d found to have a superior anticancer activity, where it has (IC50 = 2.07 ± 0.13 μg/mL) in comparison with the reference drug doxorubicin that has (IC50 = 2.79 ± 0.07 μg / mL). Then compound 5d subjected to further studies such as cell cycle analysis and apoptosis. Apoptosis was confirmed by the upregulation of Bax, downregulation of Bcl-2, and the increase of the caspase 3/7percentage. Conclusion: Insertion of pyrazole, oxadiazole and, quinazoline moieties with 2-thiohydantoin moiety led to the enhancement of its anti-proliferative activity. Hence they can be used as anticancer agents.