Mini Reviews in Medicinal Chemistry - Volume 18, Issue 8, 2018

This review brings forth the potential of thiazole derivatives for their anticancer activities. The emphasis is placed on the structural diversity of thiazole derivatives, responsible for their specific anticancer activity. Multiple classes of thiazole derivatives such as Schiff base, mono-, di-, tri-, and heterocyclic substituents that possess anticancer activity have been exemplified. Molecular modelling of compounds that predicts enhanced anticancer activity of the modified structures has also been elaborated in the review. Significant advancements in synthetic chemistry related to cytotoxicity can now better position the drug discovery team to undertake thiazoles as valuable leads. The beneficial thiazole derivatives possessing anticancer activity will reignite the interest of medicinal chemists in thiazole and their derivatives.

Inosine-5′-monophosphate dehydrogenase (IMPDH) is a metabolic enzyme that catalyzes the critical step in guanine nucleotide biosynthesis, and thus is at the center of cell growth and proliferation. However, although this enzyme has been exploited as potential target for the development of immunosuppressive, anticancer, and antiviral agents, the functional importance of IMPDH as a promising antiprotozoan drug target is still in its infancy mainly because of the availability of alternative nucleotides metabolic pathways in many of these parasites. This situation suggests that the inhibition of IMPDH might have little to no effect on the survival of protozoan parasites. As a result, no IMPDH inhibitor is currently commercially available or has advanced to clinical trials as a potential antiprotozoan drug. Nevertheless, recent advances toward the development of selective inhibitors of the IMPDH enzyme from Crystosporidium parvum as potential drug candidates against cryptosporidiosis should revive further investigations of this drug target in other protozoa parasites. The current review examines the chemical structures and biological activities of reported protozoan's IMPDH inhibitors. SciFinder was used to broadly pinpoint reports published on the topic in the chemical literature, with no specific time frame. Opportunities and challenges towards the development of inhibitors of IMPDH enzymes from protozoa parasites as potential chemotherapies toward the respective diseases they cause are also discussed.

Lipases are enzymes that catalyse the hydrolysis of ester bonds of triglycerides ranging among biocatalysts of considerable physiological significance and industrial potential. Better understanding of the catalytic functions and achieving the possibility to control the biocatalysis process, in particular exploring some activators and inhibitors of lipases, seems to be crucial in the context of novel applications. The lipase activity is a function of interfacial composition: the enzyme can be there activated as well as denaturated or deactivated and the interface is an appropriate site for modulating lipolysis. Lipase inhibitor, interacts directly with the enzyme and inhibits lipase action. Alternatively, some compounds can postpone the lipolytic reaction via adsorption to the interphase or to the substrate molecules. The aim of this review is to summarise the current knowledge concerning human, animal and microbial lipase inhibitors, which were grouped into two categories: synthetic lipase inhibitors (including phosphonates, boronic acids and fats analogues) and natural compounds (including β-lactones and some botanical foodstuffs – plant extracts and plant metabolites, mainly polyphenols and saponins as well as peptides and some dietary fibers). The topics discussed include also inhibition issues from the viewpoint of obesity treatment. Among natural compounds able to inhibit lipase activity are β- lactones including orlistat. Orlistat is the only registered drug for obesity treatment in many countries and lipases are essential enzymes for lipid absorption – thus fat absorption or obesity can be controlled by lipase inhibition, especially pancreatic lipase which is responsible for the hydrolysis of over 80% of total dietary fats. Its effectiveness in obesity treatment was also described.

Asthma is an inflammatory disease which affects millions of people worldwide. Therefore, it is necessary to search for new sources of therapies for the treatment of these patients in order to improve their quality of life. From content analysis of literature of new therapeutic targets, there are various targets and drugs reported to be promising for the treatment of asthma. Interleukins involved in inflammatory processes are often presented as candidate targets for new drugs. The action of such therapeutics would not only affect interleukins, but also their receptors. Small molecules (e.g. ligustrazine and SP600125) and large molecule antibodies (e.g. lebrikizumab, benralizumab, dupilumab) are being considered as novel agents for the pharmacotherapy of asthma. Therefore, through this research, we can see advances in the search for new targets and promising drugs to treat asthma. It is expected that these new drug candidates will eventually be approved and marketed so that asthma patients can use them to enhance their quality of life.

The incidence of diabetes mellitus (DM) has increased globally. Various complications such as blindness, nephropathy leading to renal failure, neuropathy, foot ulceration, amputation, and disturbance in autonomic nervous system were reported. Although, allopathy treatment still remains the treatment of choice, there is a need to look at the easy availability, patient compliance and cheaper cost of the drugs used in day-day practice. In this regard, complementary and alternative medicine has a greater role to play. Numerous plant extracts were shown to exhibit antihyperglycemic properties. In the present review, we surfed published literature in Pubmed and google databases with regard to the herbs used for DM wound treatment. We also discuss the possible mechanism of wound healing in DM with regard to advanced glycation end products, inflammation, macrophages, non-leukocytic cells such as keratinocytes, fibroblasts and endothelial cells, matrix metalloproteinase and miRNA. The review opens the door for effective treatment of DM wounds with plant extracts and plan future treatment options.

Background: Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drugs for the treatment of AD. Objective: our aim in this article was to investigate the inhibitory potential of five known compounds (2-6) with spiro skeleton against AChE and BChE using ELISA microplate assays. In addition to their ChE inhibitory effect, their physico-chemical properties were also calculated. Moreover, the present work aims at investigating the charge/geometrical effect of a hypothetical pharmacophore or bidentate site in a bioactive group, on the inhibition efficiency of spiro compounds 2-6 by using Petra/Osiris/ molinspiration (POM) and X-ray analyses. Method: In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested in vitro for their inhibitory potential against AChE and BChE using ELISA microtiter plate assays at 25 μg/mL. Results: Results revealed that three of the spiro compounds tested exert more than 50% inhibition against one of cholinesterases. Compound 5 displayed 68.73 ± 4.73% of inhibition toward AChE, whereas compound 6 showed 56.17 ± 0.83% of inhibition toward BChE; these two previously synthesized compounds have been the most active hits. Conclusions: Our data obtained from screening of compounds 2-6 against the two cholinesterases indicate that three of these show good potential to selectively inhibit AChE or BChE. Spiro compounds 2, 5, and 6 exhibited the most potent activity of the series against AChE or BChE with inhibition values in the range 55-70%.

Background: In this study, synthesis, molecular docking and anticancer screening of new series of substituted heterocycles with trimethoxy phenyl scaffold as Combretastatin analogues were described. Substituted pyridines were synthesized via the reaction of (E)-3-(dimethylamino)-1-(3,4,5- trimethoxyphenyl)prop-2-en-1-one (2) with active methylene reagents. Substituted pyrimidines were prepared by the reaction of the enaminone (2) with heterocyclic amines and 6-amino thiouracil. Furthermore, a series of pyrazoles substituted with trimethoxyphenyl scaffold were prepared by the reaction of the enaminone 2, with selected examples of hydrazonoyl halides. Conclusion: The cytotoxic effect of the newly compounds was evaluated against HePG-2, HCT-116, MCF-7 and PC3 cancer cell lines. Among the new products, compounds 2, 3, 7 and 10 were found to exhibit promising results as anticancer agents. The IC50 values of 2, 3 and 7 were 54.6, 77.4 and 47.4 on PC3 respectively. Also, compound 2 had IC50 28.06 on MCF7. Moreover, the selectivity index indicated that compounds 2 and 3 are safe.