Medicinal Chemistry - Volume 19, Issue 6, 2023

Excessive and uncontrolled oxidative stress can damage biomacromolecules, such as lipids, proteins, carbohydrates, and DNA, by free radical and oxidant overproduction. In this review, we critically discuss the main properties of free radicals, their implications in oxidative stress, and specific pathological conditions. In clinical medicine, oxidative stress can play a role in several chronic noncommunicable diseases, such as diabetes mellitus, cardiovascular, inflammatory, neurodegenerative diseases, and tumours. Antioxidant supplements can theoretically prevent or stop the progression of diseases, but a careful literature analysis finds that more evidence is needed to dissect the ultimate beneficial effect of antioxidants versus reactive oxygen species in several diseases.

Cancer is a deadly human disease on the rise due to changes in lifestyle, nutrition, and global warming. Cancer is characterized by uncontrolled, disordered, and undesired cell division. About 60% of cancer medicines approved by the FDA are made from natural ingredients. Intensive efforts over the last decade to better understand the vast chemical diversity provided by marine life have resulted in an intriguing "marine pipeline" of potential anticancer clinical and preclinical treatments. The molecular targets of marine products as anticancer drugs, as well as different reported compounds acting on distinct targets, are the topic of this review.

Background: For years, plant materials collected from members of the family Rutaceae have been the subject of various phytochemical and pharmacological studies. In such works, skimmianine (SM) is a secondary metabolite type furoquinoline alkaloid, which can be seen as a major component available in medicinal plants of the family Rutaceae. Although there have been numerous phytochemical and biological experiments, a brief review of this compound is insufficient. Objective: The current review with the most aim is to provide information on its natural occurrence, structural features, biosynthesis, synthesis, pharmacological values, and pharmacokinetic action. Methods: The list of references was gathered from the following databases: Google Scholar, Pub- Med, Scopus, Web of Science, Science Direct, and Medline. In the meantime, "skimmianine" either alone, or combined "phytochemistry", "biosynthesis", "synthesis", "pharmacology", and "pharmacokinetics" was taken into consideration, to search for references. Results: Accumulative evidence indicated that many Rutaceae plants, such as genus Zanthoxylum, were associated with the presence of alkaloid SM. Biosynthesis of organic hetero-tricyclic compound SM started from anthranilic acid, whereas its short synthetic steps were initially derived from 2,4,7,8- tetramethoxyquinoline. SM established a great role in pharmaceutical aspect since it possessed antimicrobial, antiparasitic, antiinsect, antiplatelet, antidiabetic, antiviral, cholinesterase inhibitory, analgesic, cardiovascular, and estrogenic activities, especially cytotoxicity and anti-inflammatory activity. Pharmacokinetic progress of SM in rats mostly involved the changes of double bond C2-C3 and methoxy groups. Conclusion: Pharmacological properties justify its usage in drug development. However, some aspects, such as the extensive mechanism of action, structure-activity relationship, toxicological, and clinical studies, demand more research.

Introduction: Alzheimer’s disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. Methods: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4- lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. Results: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. Conclusion: Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.

Several chromene derivatives have a wide variety of biological and pharmacological activity. They had anticancer activity, antimicrobial activity, antituberculosis activity, anticonvulsant activity, antidiabetic activity, antichlolinesterase activity, and inhibitor of monoamine oxidase activity. The above-mentioned activities directed us to synthesize novel chromene derivatives, chromeno[2,3-d][1,3]oxazines, and chromeno[2,3-d]pyrimidines. The starting material was 2- amino-8-(2-chlorobenzylidene)-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. Methods: Several novel chromene derivatives had been synthesized. Compound 1 reacted with carbon disulfide, and ethyl chloroformate to afford chromene derivatives 2, 3. Chromene derivative 3 reacted with hydrazine dydrate to give compound 4. Chromene derivative 1 reacted with acetic acid and sulphuric acid to produce compounds 5, and 6. Amino derivative 5 reacted with chloroacyl derivative to afford compounds 7a-c which cycalized in dry xylene to afford compounds 8a-c. Chromene derivative 8a reacted with hydroxyl amine to afford compound 9. Results: The structures of novel synthesized chromene derivatives had been confirmed using mass spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis. Most of the prepared compounds were screened against liver cancer cell lines (HepG-2), human colon cancer cell lines (HT-29), and breast adenocarcinoma cell lines (MCF-7). Chromene derivative 2 had anticancer activity against human colon cancer cell lines (HT-29) higher than the reference drug doxorubicin. The rest of the tested compounds had anticancer activity against human colon cancer cell lines (HT-29) lower than that of the reference drug doxorubicin. Chromene derivative 5 had anticancer activity against liver cancer cell lines (HepG-2) higher than the reference drug doxorubicin. Conclusion: Several chromene derivatives had been synthesized and their structures had been confirmed using different spectroscopic techniques. Some of the chromene derivatives that were screened against different cancer cell lines showed promising anticancer activity higher than the reference standard drug. For example, chromene derivative 2 had anticancer activity against human colon cancer cell lines (HT-29) higher than the reference drug doxorubicin. Chromene derivative 5 had anticancer activity against liver cancer cell lines (HepG-2) higher than the reference drug doxorubicin. Chromene derivative 6 had anticancer activity against breast adenocarcinoma cell lines (MCF-7) higher than the standard drug.

Some species of Marine bacteria pose great risks to human and mariculture organisms. Meanwhile, Vibrio harveyi and Vibrio parahaemolyticus strains have acquired resistance to many antibiotics. Objective: A novel series of erythromycin 9-acylhydrazone derivatives were synthesized and evaluated for their in vitro antibacterial activity against marine pathogens. Methods: The site-selective N-acylation of erythromycin hydrazone was achieved using acid chloride/ triethylamine in methanol as the reaction system. All the synthesized target compounds were evaluated for their antibacterial activity by determination of minimum inhibitory concentrations (MICs) using the broth microdilution method. Results: All the tested acylhydrazone compounds showed moderate to high activity with MIC value 0.125-1 μg/mL against Vibrio parahaemolyticus and Vibrio harveyi. Conclusion: The introduction of the acylhydrazone moiety at the C-9 position of erythromycin improved its activity against the above-mentioned marine bacteria strains.

Introduction: The nuclear transcription factor PPARγ, which can modulate cell growth via proliferation and apoptosis-related mechanisms, is a promising target in cancer therapy. This study aims to focus on PPARγ as the target and use virtual screening to find hits. Methods: A set of 5,677 flavonoid compounds were filtered by subjecting them to descriptor-based drug-likeness and ADMET strategies to discover drug-like compounds. The candidates' modes of binding to PPARγ were then evaluated using docking and MD simulation. PharmMapper was used to identify the potential targets of selected hits. The pharmacological network was constructed based on the GO and KEGG pathway analysis. Results: In primary screening, 3,057 compounds met various drug-likeness criteria and docked well as partial agonists in the PPARγ-LBD. Five compounds (euchrenone b1, kaempferol-7-Orhamnoside, vincetoxicoside B, morusin, and karanjin) were selected with the use of ADMET profiles for further MD simulation investigation. Based on the PharmMapper findings, 52 proteins were then submitted to GO and KEGG enrichment analysis. As expected by GO and KEGG pathway enrichment studies, core targets were enriched in the PI3K-Akt signaling pathway (p < 0.01), indicating that certain chemicals may be involved in cancer processes. Conclusion: Our results suggested that the selected compounds might have sufficient drug-likeness, pharmacokinetics, and in silico bioactivity by acting as PPARγ partial agonists. Although much work remains to illuminate extensive cancer therapeutic/ chemopreventive efficacy of flavonoids in vivo, in silico methodology of our cheminformatics research may be able to provide additional data regarding the efficacy and safety of potential candidates for therapeutic targets.