Combinatorial Chemistry & High Throughput Screening - Volume 23, Issue 9, 2020

Multi-functional design of ligands emerged as a new drug design paradigm of Alzheimer's disease (AD). Given the complexity of AD, the molecules showing dual inhibition of monoamine oxidase (MAO) and acetylcholinesterase (AChE) with neuroprotective properties could prevent the progressive neural degeneration effectively. Numerous studies documented that chalcone is a privileged structural framework for the inhibition of both MAO and AChE. The recent studies suggested that the development of chalcone candidates endowed with pharmacophores of FDA approved drugs may become an active molecules in the field of current AD research. The current perspective described the recent updates of chalcone moiety linked with the pharmacophores of flurbiprofen and rivastigmine hybrids as selective ChE/MAO-B inhibitors for the prophylactic agents for AD.

Background: One of the most prevalent neurodegenerative diseases with increasing age is Parkinson’s disease (PD). Its pathogenesis is unclear and mainly confined to glutamate toxicity and oxidative stress. The dyskinesia and motor fluctuations and neuroprotective potential are the major concerns which are still unmet in PD therapy. Objective: This article is a capsulization of the role of MAO-B in the treatment of PD, pharmacological properties, safety and efficiency, clinical evidence through random trials, future therapies and challenges. Conclusion: MAO-B inhibitors are well tolerated for the treatment of PD because of their pharmacokinetic properties and neuroprotective action. Rasagiline and selegiline were recommended molecules for early PD and proven safe and provide a modest to significant rise in motor function, delay the use of levodopa and used in early PD. Moreover, safinamide is antiglutamatergic in action. When added to Levodopa, these molecules significantly reduce the offtime with a considerable improvement of non-motor symptoms. This review also discusses the new approaches in therapy like the use of biomarkers, neurorestorative growth factors, gene therapy, neuroimaging, neural transplantation, and nanotechnology. Clinical evidence illustrated that MAOB inhibitors are recommended as monotherapy and added on therapy to levodopa. A large study and further evidence are required in the field of future therapies to unwind the complexity of the disease.

With respect to the unknowns of pathophysiology of Alzheimer’s Disease (AD)-, and Parkinson's Disease (PD)-like neurodegenerative disorders, natural product research is still one of the valid tools in order to provide alternative and/or better treatment options. At one hand, various extracts of herbals provide a combination of actions targeting multiple receptors, on the other hand, the discovery of active natural products (i.e., secondary metabolites) generally offers alternative chemical structures either ready to be employed in clinical studies or available to be utilized as important scaffolds for the design of novel agents. Regarding the importance of certain enzymes (e.g. cholinesterase and monoamine oxidase B), for the treatment of AD and PD, we have surveyed the natural product research within this area in the last decade. Particularly novel natural agents discovered within this period, concomitant to novel biological activities displayed for known natural products, are harmonized within the present study.

Background: Monoamine oxidase and cholinesterase enzymes are very critical enzymes that regulate the level of neurotransmitters such as acetylcholine and monoamines. Monoamine neurotransmitters and acetylcholine play a very important role in many physiological events. An increase or decrease in the amount of these neurotransmitters is observed in a wide range of central nervous system pathologies. Balancing the amount of these neurotransmitters is important in improving the progression of these diseases. Inhibitors of monoamine oxidase and cholinesterase enzymes are important in symptomatic therapy and delaying progression of a group of central nervous system disease manifested with memory loss, cognitive decline and psychiatric disturbances like depression. Objective: In this article, the relationship between central nervous system diseases and the vital role of the enzymes, monoamine oxidase and cholinesterase, is discussed on the pathophysiologic basis, focusing on drug research. Conclusion: Monoamine oxidase and cholinesterase enzymes are still a good target for the development of novel drug active substances with optimized pharmacokinetic and pharmacodynamic properties, which can maximize the benefits of current therapy modalities.

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson’s disease, and Alzheimer’s disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.

Background: Monoamine oxidases (MAOs) play a crucial role during the development of various neurodegenerative disorders. There are two MAO isozymes, MAO-A and MAO-B. MAO-A is a flavoenzyme, which binds to the outer mitochondrial membrane and catalyzes the oxidative transformations of neurotransmitters like serotonin, norepinephrine, and dopamine. Materials and Methods: Focus on synthetic studies has culminated in the preparation of many MAOA inhibitors, and advancements in combinatorial and parallel synthesis have accelerated the developments of synthetic schemes. Here, we provided an overview of the synthetic protocols employed to prepare different classes of MAO-A inhibitors. We classified these inhibitors according to their molecular scaffolds and the synthetic methods used. Results: Various synthetic and natural derivatives from a different class of MAO-A inhibitors were reported. Conclusion: The review provides a valuable tool for the development of a new class of various selective MAO-A inhibitors for the treatment of depression and other anxiety disorders.

Aim and Objective: The present study was designed to evaluate the xanthine oxidase (XO) inhibitory and antioxidant activities of 30 bioactive compounds present in edible food plants for the possible treatment of hyperuricemia. Materials and Methods: The XO inhibitory, SO and DPPH radical scavenging activities of selected dietary polyphenols were determined by using colorimetric assays. The molecular docking analysis was performed to evaluate the insight into inhibitory mode of action of bioactive compounds against XO. Results: The results show that apigenin, galangin, kaempferol, quercetin, genistein and resveratrol potently inhibit XO enzyme among all tested compounds. Flavonoids exhibit higher, anthocyanins and hydroxycinnamic acids moderate, maslinic acid, ellagic acid, salicylic acid, [6]-gingerol and flavan-3-ols showed weak XO inhibitory activity. The results of molecular docking study revealed that these bioactive compounds bind with the active site of XO and occupy the active site which further prevents the entrance of substrate and results in the inhibition of XO. Conclusion: Inhibition of XO gives a robust biochemical basis for management of hyperuricemia, gout and other associated diseases via controlling uric acid synthesis.

Background: Inflammation and pain, mainly induced by the prostaglandins synthesized by the cyclooxygenase enzymes, may cause distress. To overcome this unpleasant stress in a safer manner, numerous natural molecules are proven for modulating the COX enzymes. Epicatechin and daidzein are two bioactive natural compounds present in horsegram, a legume known for its medicinal properties. Objective: The present study aims at evaluating the potential of horsegram, and some of its bioactive molecules, to be used as an anti-inflammatory and analgesic agent mediated by the inhibition of COX enzymes, which can be recommended as a substitute for chemically synthesized NSAIDs. Methods: The present work involved the quantification of epicatechin and daidzein present in horsegram seeds. The COX enzyme inhibitory nature of epicatechin and daidzein was tested using in silico docking analysis with Autodock software and was further confirmed by in vitro COX inhibitory biochemical assays. Furthermore, the anti-inflammatory and analgesic activities of the horsegram seeds were evaluated in animal experiments. Results: Horsegram seeds contain 158.1 microgram/g and 6.51 microgram/g of epicatechin and daidzein respectively. The docking studies reveal that both the bioactive molecules exhibit better binding efficiency with COX-2 protein as compared to COX-1. Hence, in vitro COX-2 inhibitory assay was performed for epicatechin, daidzein and compared with known analgesic agent diclofenac which revealed a pronounced dose dependent inhibitory activity. Furthermore, the analgesic and anti-inflammatory activity of horsegram in experimental animals exhibited a dose dependent effect which might be due to the presence of the bioactive compounds such as epicatechin and daidzein. Conclusion: The results suggest that epicatechin and daidzein present in horsegram are potent cyclooxygenase inhibitors and thus would be helpful in the management of inflammation and pain.

Background: Propolis is a resinous mixture collected by honeybees from tree buds and exudates of the plants. Propolis contains aromatic acids, diterpenic acids and phenolic compounds and these components are responsible for its antitumor, anticancer, antiviral and antifungal effects. Propolis can be extracted and the solubility of propolis differs depending on the solvent used in the process of extraction. Solvents used for propolis extraction have a great impact on the propolis extract and should be nontoxic. Objective: In this study, raw propolis was extracted by peppermint and clove volatile oils. Methods: Chemical composition of extracts was determined by using GC-MS equipment. Total phenolic content and antioxidant activity of the extracts were measured. α-amylase inhibitory activity of the extracts was carried out as well. Results: The findings of the present study showed that clove volatile oil is more effective in the extraction of propolis than peppermint volatile oil. The total phenolic content of these extracts was determined as 175.12 and 40.80 mg GAE/mL for clove and peppermint oil propolis extracts, respectively. All extracts contained the same phenolic compounds but the quantity was less in volatile oil extract than in ethanol extract. Both of these extracts showed better α-amylase ınhibitory activity than a reference inhibitor, acarbose. Conclusion: It could be concluded that propolis extract obtained by using volatile oils could be used as a complementary agent in the treatment of type 2 diabetes mellitus.

Background: Avicennia alba Blume, is a well-known mangrove plant used in traditional medicinal practices for several human ailments. Objective: The study aimed at the evaluation of antidiabetic, antioxidant, anti-inflammatory and cytotoxic activities of A. alba ethanolic leaf (AAL) and bark (AAB) extract along with phytochemical investigation. Methods: In vitro antidiabetic study was done by α-amylase, α-glucosidase enzyme inhibition assay; antioxidant study by DPPH, ABTS, superoxide, and metal chelating assays, antiinflammatory study by protein denaturation assay. The cytotoxicity study was done on TC1 murine cell line. Further, GC-MS analysis was carried out for AAL extracts. Results: AAL exhibited better antidiabetic activities with IC50 values of 1.18 and 0.87 mg/ml against α-amylase and α-glucosidase enzymes respectively. The AAL exhibited better ABTS, superoxide scavenging and metal chelating potential with IC50 values of 0.095, 0.127 and 0.444 mg/ml. However, AAB showed higher DPPH scavenging potential with IC50 value of 0.163 mg/ml. The AAL also exhibited higher protein denaturation potential with IC50 value of 0.370 mg/ml. The bark extract exhibited better cytotoxic activity as compared to leaf extracts on the TC1 murine cell line. The phytochemical study revealed higher total phenol (25.64 mg GAE/g), flavonoid (205.09 mg QE/g), and tannin content (251.17 mg GAE/g) in AAL. The GC-MS analysis revealed the presence of several compounds in AAL extract. Conclusion: The result of the present study highlights the antidiabetic, antioxidant and cytotoxic activities of mangrove plant Avicennia alba.

Background and Objective: Mycoplasmal pneumonia (MP) can lead to inflammation, multiple system immune damage, and mixed infection in children. The pathogenesis is still unclear. Shuang-Huang-Lian (SHL) oral liquid can treat acute upper respiratory tract infection, acute bronchitis and light pneumonia. However, our current understanding of the molecular mechanisms supporting its clinical application still lags behind due to the lack of researches. It is difficult to understand the overall sensitization mechanism of SHL oral liquid. The purpose is to explain the mechanism of action of drugs in this study, which is useful to ensure the safety of medication for children. Methods: The therapeutic mechanism of SHL oral liquid was investigated by a system pharmacology approach integrating drug-likeness evaluation, oral bioavailability prediction, ADMET, protein-protein interaction worknet, Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes database pathway performance, C-T-P network construction and molecular docking. Results: A total of 18 active ingredients contained in SHL oral liquid and 53 major proteins were screened out as effective players in the treatment of M. pneumoniae disease through some related pathways and molecular docking. The majority of targets, hubs and pathways were highly related to anti-mycoplasma therapy, immunity and inflammation process. Conclusion: This study shows that the anti-bacterial effect of SHL oral liquid has multicomponent, multi-target and multi-pathway phenomena. The proposed approach may provide a feasible tool to clarify the mechanism of traditional Chinese medicines and further develop their therapeutic potentials.

Aim and Objective: Humans continuously use pesticides in the field to control the pest population and weeds for considerable agricultural productivity. Side-by species like grazinganimals, insects and other species are adversely affected by or become resistant to pesticides. Insects, birds and cattle are highly abundant dwellers of the agriculture-field and represent three distinct phyla having versatile physiological features. Besides higher agricultural-productivity, protection to several species will maintain ecological/environmental balance. Studies on the effect of widely used pesticides on their DNA-stability and important enzymatic-activities are insufficient. Materials and Methods: Antioxidant-activity (Superoxide-dismutase; SOD/Catalase- by gelzymogram- assay) and DNA-stability (fragmentation-assay) in hepatic/gut tissues were studied after in vitro exposure of Chlorpyrifos, Fenvalerate, Nimbecidine or Azadirachtin to goat/cow/poultry-hen/insect. Results: In general, all pesticides were found to impair enzymatic-activities. However, lower organisms were affected more than higher vertebrates by azadirachtin-treatment. DNA fragmentation was found more in insects/poultry-birds than that of the cattle in hepatic/gut tissues. Inversely, toxicity/antioxidant marker-enzymes were more responsive in insect gut-tissues. However, mitochondrialtoxicity revealed variable effects on different species. It has been noticed that chlorpyrifos is the most toxic pesticide, followed by Fenvalerate/Nimbecidine (Azadirachtin, AZT). Nevertheless, AZT revealed its higher DNA-destabilizing effects on the field-insects as compared to the other animals. Conclusion: Field-insects are highly integrated into the ecosystem and the local bio-geo-chemical cycle, which may be impaired. Pesticides may have toxic effects on higher vertebrates and may sustain in the soil after being metabolized into their different derivatives. Some of the sensitive biochemical parameters of this organism may be used as a biomarker for pesticide toxicity.

Background and Objective: The SOX2OT lcnRNA has been recognized as a positive regulator in the transcription regulation of the SOX2 gene. Recent studies have approved the dysregulation of SOX2OT lncRNA expression patterns in some common cancer types, including esophageal, lung, and breast cancer. The objective of the present study was to investigate the correlation between overexpression of SOX2OT lcnRNA and susceptibility to breast cancer.

Methods: SOX2OT lncRNA expression profiling in 15 breast cancer and normal tumour-adjacent breast tissue samples was performed by using qRT-PCR. To evaluate the diagnostic potential of the SOX2OT lncRNA, we performed ROC curve analyses.

Results: The expression of SOX2OT lncRNA in patients suffering from breast cancer revealed a significant overexpression in comparison with the healthy group (P<0.001). Significantly, the elevated circulating SOX2OT lncRNA was found specific to breast cancer and could differentiate breast cancer from controls with 100% of both sensitivity and specificity. Based on the Kaplan- Meier analysis, there was no significant correlation between SOX2OT lcnRNA expression and overall survival.

Conclusion: The results confirmed the association between breast cancer and higher SOX2OT lncRNA expression. According to the ROC curve results, SOX2OT lcnRNA could be a new measurable indicator of the breast cancer and a potential therapeutic target for breast cancer patients.