Letters in Drug Design & Discovery - Volume 16, Issue 10, 2019

The article discusses the basic properties of fluorine atom that have made it so useful in drug development. It presents several examples of therapeutically useful drugs acting against many life-threatening diseases along with the mechanism as to how fluorine influences the drug activity. It has been pointed out that fluorine, due to its ability to increase the lipophilicity of the molecule, greatly affects the hydrophobic interaction between the drug molecule and the receptor. Because of its small size, it hardly produces any steric effect, rather due to electronic properties enters into electrostatic and hydrogen-bond interactions. Thus, it greatly affects the drug-receptor interaction and leads to increase the activity of the drugs.

Background: Human tumor cells lines and tumor samples overexpress the neurokinin-1 receptor (NK-1R). Substance P (SP), after binding to NK-1Rs, induces tumor cell proliferation, an antiapoptotic effect and promotes angiogenesis and the migration of cancer cells for invasion and metastasis. Methods: In contrast, NK-1R antagonists block the previous pathophysiological actions mediated by SP. These antagonists promote the death of tumor cells by apoptosis. Peptide and non-peptide NK-1R antagonists have been reported. Results: Peptide NK-1R antagonists show chemical modifications of the SP molecule (L-amino acids being replaced by D-amino acids), whereas non-peptide NK-1R antagonists include numerous compounds with different chemical compositions while showing similar stereochemical features (affinity for the NK- 1R). Currently, there are more than 300 NK-1R antagonists. Conclusion: In combination therapy with classic cytostatics, NK-1R antagonists have additive or synergic effects and minimize the side-effects of cytostatics. The effect of NK-1R antagonists as broad-spectrum anticancer drugs is reviewed and the use of these antagonists for the treatment of cancer is suggested.

High cholesterol and triglyceride levels are mainly related to further generation of lifethreating metabolism disorders including cardiovascular system diseases. Therefore, hypercholesterolemia (i.e., also referred to as hyperlipoproteinemia) is a serious disease state, which must be controlled. Currently, the treatment of hypercholesterolemia is mainly achieved through the employment of statins in the clinic, although there are alternative drugs (e.g., ezetimibe, cholestyramine). In fact, the original statins are natural products directly obtained from fungi-like molds and mushrooms and they are potent inhibitors of hydroxymethylglutaryl-CoA reductase, the key enzyme in the biosynthesis of cholesterol. This review focuses on the first identification of natural statins, their synthetic and semi-synthetic analogues, and the validation of hydroxymethylglutaryl-CoA reductase as a target in the treatment of hypercholesterolemia. Furthermore, other natural products that have been shown to possess the potential to inhibit hydroxymethylglutaryl-CoA reductase are also reviewed with respect to their chemical structures.

Dietary fatty acids have exerted numerous pathophysiological effects in humans. Indeed, monounsaturated fatty acids and ω-3 polyunsaturated fatty acids are generally thought to have favorable cardiometabolic actions via their anti-inflammatory and anti-thrombotic properties, while saturated fatty acids and trans fatty acids are supposed to contribute to the development and progression of atherosclerotic cardiovascular diseases by inducing dyslipidemia and obesity. However, there is much controversy about the effects of dietary intake and supplementation of fatty acids on cardiometabolic disorders. Therefore, in the present study, we limited the scope of this review to metaanalyses (1) of observational studies of dietary intake of fatty acids and (2) of interventional trials with fatty acid supplements to scrutinize the role of fatty acids in various cardiometabolic disorders. We discuss here the clinical effects of fatty acids from dietary intake or supplements on incidence of diabetes, metabolic syndrome, obesity and body weight, cardiovascular diseases and total mortality, and also review the association of fatty acid biomarkers with these cardiometabolic disorders.

Coffee, one of the world’s most consumed products, is extracted from the roasted seeds of Coffea sp., a plant native to Africa. The effects of coffee on the human body have been recognized for centuries and have now become the subject of systematic research. Caffeine’s impact on a person’s cognitive ability was reviewed through a large set of literature related to the subject. Learning and memory tasks are not typically influenced by caffeine when it comes to performance. However, in some cases, it has been used to produce inhibitory or facilitatory effects on learning and/or memory. Caffeine facilitates performance in tasks involving the working memory, but it has been seen that tasks that rely on working memory may be hindered because of it. Moreover, caffeine can augment the performance of memory during times where a person’s alertness is suboptimal at best. However, a large body of research points to an improvement in reaction time. Consuming it has little to no impact on long-term memory. Caffeine can be taken as a mild stimulant, proven by its effect on performance in the context of subjects who are tired or fatigued. In some cases, it has been observed that caffeine prevents cognitive decline, specifically when it comes to healthy subjects; however, these results are heterogeneous at best. While drinking coffee positively influences both physical and mental capacity, caffeine cannot and should not be viewed as an “absolute” enhancer of cognitive function. Existing literature shows that the impact it causes on an individual is complex, and can alter, for example, anxiety, performance and arousal.

Background: A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties. Methods: The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes. Results: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib. Conclusion: Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

Background: One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

Background: As the first phenylpyrazole pesticide, fipronil has been widely used in crop protection and public hygiene. In the low energy conformation of fipronil, a pseudo-six-membered ring is observed through an intramolecular hydrogen bond. Methods: A scaffold hopping strategy was applied to mimic the pseudo-six-membered ring of fipronil by non-aromatic ring. All compounds were synthesized with a proper synthetic route and characterized by 1H NMR, 13C NMR and high-resolution mass spectra. Insecticidal activities of all target compounds against Plutella xylostella were assessed by a professional organization. Physicochemical property prediction and docking study of these compounds with GABA receptor were also performed. Results: A series of 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine derivatives containing twenty-five compounds were designed, synthesized and evaluated. Several compounds exhibited moderate activities against Plutella xylostella. The strong electron-withdrawing groups are conducive to improve activities of this series of compounds against Plutella xylostella. Docking study showed that the most active compound 10 with nitro group could bind within the TM2 domain of GABA receptor, in which a hydrogen bond was observed with residue 6’Thr. The activity of 10 was weaker than fipronil due to the differences in physicochemical properties. Conclusion: More attention should be paid to physicochemical properties during novel pesticide hit or lead design through scaffold hopping.