Mini Reviews in Medicinal Chemistry - Volume 20, Issue 11, 2020

Natural products form a significant portion of medicinal agents that are currently used for the management of cancer. All these natural products have unique structures along with diverse action mechanisms with the capacity to interact with different therapeutic targets of several complex disorders. Although plants contribute as a major source of natural products with anti-cancer potential, the marine environment and microbes have also bestowed some substantial chemotherapeutic agents. A few examples of anti-cancer agents of natural origin include vincristine, vinblastine, paclitaxel, camptothecin and topotecan obtained from plants, bryostatins, sarcodictyin and cytarabine from marine organisms and bleomycin and doxorubicin from micro-organisms (dactinomycin, bleomycin and doxorubicin). The incredible diversity in the chemical structures and biological properties of compounds obtained from million species of plants, marine organisms and microorganisms present in nature has commenced a new era of potential therapeutic anti-cancer agents.

Medicinal plants have a wide range of secondary metabolites including monoterpene. These volatile compounds are the main components of essential oils, belonging to the isoprenoid group and possessing valuable features for plants and humans. This review provides comprehensive information on chemical structures and classification of monoterpenes. It describes their biosynthesis pathways and introduces plant families and species rich in noteworthy monoterpenes. Bio-activities, pharmacological and pesticide effects as well as their mechanism of action are reported. Applications of these compounds in various industries are also included.

Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux in the distal oesophagus, and this may cause the development of reflux esophagitis and Barrett’s oesophagus (BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and High-Grade Dysplastic (HGD) BE, with the expected increase in malignancy transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution white-light endoscopy, followed by uniform endoscopy findings description (Prague classification) with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE includes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of resection and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and prevention of its transfer to EAC.

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non-toxic chemical that mediates anti-inflammatory effects by down-regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.

Hybrid materials based on Mesoporous Silica Nanoparticles (MSN) have attracted plentiful attention due to the versatility of their chemistry, and the field of Drug Delivery Systems (DDS) is not an exception. MSN present desirable biocompatibility, high surface area values, and a well-studied surface reactivity for tailoring a vast diversity of chemical moieties. Particularly important for DDS applications is the use of external stimuli for drug release. In this context, light is an exceptional alternative due to its high degree of spatiotemporal precision and non-invasive character, and a large number of promising DDS based on photoswitchable properties of azobenzenes have been recently reported. This review covers the recent advances in design of DDS using light as an external stimulus mostly based on literature published within last years with an emphasis on usually overlooked underlying chemistry, photophysical properties, and supramolecular complexation of azobenzenes.

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

Background & Objective: Comparative molecular field analysis (CoMFA) of 27 analogues of 2-((pyridin-3-yloxy)methyl)piperazine derivatives was carried out using software Tripos SYBYL X. Optimal r2 (0.854) and q2 (0.541) values were obtained for the developed 3D-QSAR model. The contour plots obtained from CoMFA analysis have shown 13.84% steric contribution and 66.14% electrostatic contribution towards an anti-inflammatory activity. Methods: The homology model of the receptor protein, α7 nicotinic acetylcholine, was generated in SWISS MODELLER using auto template mode and was analysed for the quality using Procheck, QMEAN Z-score, Anolea and GROMOS plots. The QMEAN score for the model was observed to be - 3.862. The generated model of alpha 7 nicotinic acetylcholine receptor was used for docking study of 27 piperazine analogues using Auto-Dock 4.2.5.1. Results: The dock score obtained from docking analysis was then correlated with experimental pIC50 values for in-silico validation of the developed CoMFA model and a good correlation was obtained with correlation coefficient (r2) value of -0.7378. Conclusion: The present investigation suggests an optimal 3D-QSAR with CoMFA model for further evaluating new chemical entities based on piperazine skeleton.

Background: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder. Objective: In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. Methods: The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman’s method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. Results: The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 μM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 μM). Conclusion: This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.