Medicinal Chemistry - Volume 16, Issue 8, 2020

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, with approximately 29 million older people suffering from this disease worldwide. This number is expected to become triple by 2050. AD is a complex and multifactorial neurodegenerative condition, characterized by complex pathology including oxidative stress, formation of aggregates of amyloid and tau, enhanced immune responses, metal deposition and disturbances in cholinesterase enzymes. There is no effective pharmacological treatment for combating the disease to date. The ineffectiveness of current pharmacological interventions in AD has led scientists to search for more safe and effective alternative therapeutic agents. Thus, natural products have become an important avenue for drug discovery in AD research. In this regard, polyphenols are natural products that have been shown to be effective in the modulation of the type of neurodegenerative changes seen in AD, suggesting a possible therapeutic role. The present review focuses on the chemistry of polyphenols, clinical studies for evaluating polyphenols as effective alternatives in AD treatment, cellular and molecular aspects of polyphenols in improving cognitive deficits and the current challenges and futuristic approaches to use polyphenols as safe and effective therapeutic agents in AD treatment.

Background: Glioblastoma is one of the most aggressive and devastating tumours of the central nervous system with short survival time. Glioblastoma usually shows fast cell proliferation and invasion of normal brain tissue causing poor prognosis. The present standard of care in patients with glioblastoma includes surgery followed by radiotherapy and temozolomide (TMZ) based chemotherapy. Unfortunately, these approaches are not sufficient to lead a favorable prognosis and survival rates. As the current approaches do not provide a long-term benefit in those patients, new alternative treatments including natural compounds, have drawn attention. Due to their natural origin, they are associated with minimum cellular toxicity towards normal cells and it has become one of the most attractive approaches to treat tumours by natural compounds or phytochemicals. Objective: In the present review, the role of natural compounds or phytochemicals in the treatment of glioblastoma describing their efficacy on various aspects of glioblastoma pathophysiology such as cell proliferation, apoptosis, cell cycle regulation, cellular signaling pathways, chemoresistance and their role in combinatorial therapeutic approaches was described. Methods: Peer-reviewed literature was extracted using Pubmed, EMBASE Ovid and Google Scholar to be reviewed in the present article. Conclusion: Preclinical data available in the literature suggest that phytochemicals hold immense potential to be translated into treatment modalities. However, further clinical studies with conclusive results are required to implement phytochemicals in treatment modalities.

Background: Suaeda is a halophytic genus belonging to the Amaranthaceae family and can survive in the high salted marsh areas of the world. Suaeda plants can biosynthesize natural substances with powerful antioxidant activity and are considered as a renewable source of energy, food, and edible oil for a larger number of populations living in the harsh environment with high salinity and drought conditions. These plants also meet folk and alternative medicines' needs. Methods: The review encompasses available scientific literature related to folk medicinal uses of Suaeda plants, their nutritional values, and chemical constituents. In addition, the biological trials applied for the Suaeda plants are also part of the review. The review covers the researches from major science literature search engines and other sites representing scientific literature, i.e., Scifinder, Google Scholar, PubMed, ScienceDirect, Scopus, and Google. The searches were programmed on the advance options available in the search engines and are latest up to November 2019. The searches were exhaustive and rechecked for accuracy. Conclusion: The study summarizes the uses of Suaeda plants as a remedy for various ailments due to their contents from the polyphenols and flavonoids. The comparatively large amounts of fixed oils, minerals, and vitamins in Suaeda plants have also made them potential renewable sources for foods.

Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as “Lou Gehrig’s disease”, a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.

Ziziphus jujuba Mill. belonging to the Rhamnaceae family, has been consumed since ancient times as a medicine and food. In the different traditional medical schools, Z. jujuba has been used to treat various diseases such as respiratory system diseases (asthma, cough, and laryngitis), gastrointestinal problems (constipation, colitis and liver diseases), as well as cardiovascular and genitourinary system diseases. From the perspective of Islamic traditional medicine (ITM), Z. jujuba fruit is an emollient, laxative, and maturative, it can purify blood and improve blood circulation, relieve internal heat and reduce inflammation. Some therapeutic uses of Z. jujuba such as antibacterial, antioxidant, sedative, hepato-protective, anti-hyperglycemic, and anti-hyperlipidemic activities have been shown in modern pharmacological studies. In the current study, traditional and ethno-medicinal uses, botany, phytochemistry and pharmacological activities of Z. jujuba were reviewed.

Background: Nuclear Magnetic Resonance (NMR) spectroscopy is a systematic science strategy utilized in pharmaceutical research, development, quality control, and research to decide the content and purity of a sample as well as its sub-atomic structure. There are several parameters working for better execution of NMR which can include chemical shifts, spin multiplicity, pH dependence, heteronuclear and homonuclear covalent network, and the atomic overhauser impact. NMR imaging offers an extensive scope of potential outcomes for the portrayal of skeletal muscle structure, function and metabolism. 1H additionally has the most noteworthy NMR affectability of any nucleus. The principle of NMR depends on the spins of atomic nuclei. The magnetic estimations rely on an unpaired electron, while NMR estimates attractive impact brought about by the turn of protons and neutrons. The nucleons have intrinsic angular momenta or spins, which is considered as basic magnet. Conclusion: The presence of atomic attraction was uncovered in the hyperfine structure of spectral lines. If the nucleus magnetic moment is put in the magnetic field, the phenomenon of space quantization can be observed and each allowed direction will have a marginally unique energy level. Invitro, high-resolution NMR spectroscopy helps to assess tumor metabolism by the investigation of body liquids like urine, blood and removed tissue specimens. In-cell NMR is a powerful technique to assess strong compounds in medication improvement to spare exploratory expenses.

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist. Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique. Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM). Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

Background: Curcumin is a safe, versatile natural product with unlimited number of biological activities and a precursor for various heterocyclic compounds. Objective: The present study was aimed to the development of a curcumin based antimicrobial reagent with high potency against gram-positive and gram-negative bacteria. Methods: Herein we report a simple and convenient one step method for synthesizing a series of 1,4-benzodiazepines via condensation cyclization reaction between curcumin and various 1,2- phenylenediamine in refluxed ethanol. Results: A series of new 1,4-benzodiazepins were synthesized and their structures were supported by FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. Synthesized 1,4-benzodiazepins were evaluated for their in vitro antimicrobial activity against gram positive (S. aureus and S. epidermidis) and gram negative (E. coli and P. aeruginosa) bacteria. They exhibited low to high potency against the tested organisms. In particular, dichlorinated 1,4-benzodiazepine 9 exhibited a remarkable potency against the gram-positive bacteria S. aureus (MIC: 3.125 μg mL-1, MBC: 12 μg mL-1). It showed a higher potency than most of the tested reference drugs. Compound 9 showed the medium activity against E. coli. Genotoxic study revealed that, benzodiazepines 9 attacked the DNA of E. coli strains and damaged it. The potency of compound 9, could be attributed to the multiple chlorine atoms present on the aromatic ring. Conclusion: Some of the synthesized curcumin based benzodiazepines showed excellent potency against gram positive bacteria. These benzodiazepines could be a great candidate as a future antimicrobial agent.

Background: Tyramine derivatives 3-16 were prepared and tested first time for their α- glucosidase (Sources: Saccharomyces cerevisiae) inhibitory activity by using an in vitro mechanismbased biochemical assay. All the compounds were found to be new, except compounds 3, 10-12 and 16. Objective: In continuation of our research to synthesize and identify potent inhibitors of α-glucosidase enzyme, we intended to synthesize new inhibitors of α-glucosidase enzyme with enhanced efficacy in order to provide the basis for the better treatment of the type-II diabetic. Methods: Tyramine (1) was allowed to react with a variety of aryl chlorides (2) to yield the corresponding amides. Synthesized compounds were then purified through normal phase column chromatography. Compounds 3-16 were then assessed for their α-glucosidase inhibitory activity in an in vitro biochemical assay. The cytotoxicity of compounds 3-16 was determined by using 3T3 mouse fibroblast cell lines. Results: Compounds 3-5, 8, 13, and 15-16 were found to be more active (IC50 = 103.1±0.46, 37.3±4.51, 56.7±4.2, 23.9±2.31, 43.6±2.88, 55.8±1.73, and 38.2±0.86 μM, respectively) than the acarbose, the standard inhibitor of α-glucosidase enzyme, (IC50= 840.0±1.73 μM). To determine the dissociation constants and mode of inhibition, the kinetic studies were also performed for compounds 4 and 8 (the most potent inhibitors). It was observed that compounds 4 and 8 possess noncompetitive properties as the inhibitors of α-glucosidase. All the compounds were found to be noncytotoxic, except 5 and 12 (IC50= 14.7± 0.24 and 6.6± 0.38 μM, respectively). Conclusion: The current study gives the facile synthesis and identification of potent inhibitors of α- glucosidase. The new inhibitors reported here may be investigated further for the designing and development of novel anti-diabetic agents.