A Computational Study of Green Tea Extracts and their Derivatives as Potential Inhibitors for Squalene Monooxygenase.

BACKGROUND: According to the World Health Organisation, cardiovascular complications have been recognized as the leading course of death between 2000 and 2019. Cardiovascular complications are caused by excess LDL cholesterol in the body or arteries that can build up to form a plaque. There are drugs currently in clinical use called statins that target HMGCoA reductase. However, these drugs result in several side effects. This work investigated using computational approaches to lower cholesterol by investigating green tea extracts as an inhibitors for squalene monooxygenase (the second-rate-controlling step in cholesterol synthesis). METHODS: Pharmacophore modeling was done to identify possible pharmacophoric sites based on the pIC50 values. The best hypothesis generated by pharmacophore modeling was further validated by atom-based 3D QSAR, where 70% of the data set was treated as the training set. Prior molecular docking ADMET studies were done to investigate the physiochemical properties of these molecules. Glide docking was performed, followed by molecular dynamics to evaluate the protein conformational changes. RESULTS: Pharmacophore results suggest that the best molecules to interact with the biological target should have at least one hydrogen acceptor (A5), two hydrogen donors (D9 and D10), and two benzene rings (R14 and R15) for green tea polyphenols and theasinensin A. ADMET result shows that all molecules in this class have low oral adsorption. Molecular docking results showed that some green tea polyphenols have good binding affinities, with most of these structures having a docking score of less than -10 kcal/mol. Molecular dynamics further illustrated that the best-docked ligands perfectly stay within the active site over a 100 ns simulation. CONCLUSION: The results obtained from this study suggest that green tea polyphenols have the potential for inhibition of squalene monooxygenase, except for theasinensin A.

13-amino derivatives of dehydrocostus lactone display greatly enhanced selective toxicity against breast cancer cells and improved binding energies to protein kinases in silico.

The biological activities of dehydrocostus lactone and its analogues are suggested to be mediated by the lactone ring and α,ß-methylene-γ-lactone. However, few studies exist on the structure-activity relationship of 13-amino derivatives of dehydrocostus latone. In this study new 13-amino derivatives of dehydrocostus lactone DHLC (1-4) were synthesized through Michael addition reactions, and were screened against three different breast cancer cell lines, namely hormone receptor positive breast cancer (MCF-7), triple-negative breast cancer (HCC70), and non-tumorigenic mammary epithelial (MCF-12A) cell lines. Dehydrocostus lactone (DHLC) exhibited IC50 values of 1.11 (selectivity index (SI) = 0.06), 24.70 (SI = 0.01) and 0.07 µM against HCC70, MCF-7 and MCF-12A cells, respectively. All the amino derivatives, except DHLC-3 displayed low micromolar IC50 values (ranging from 0.07-4.24 µM) against both breast cancer cell lines, with reduced toxicity towards MCF-12A non-tumorigenic mammary epithelial cells (SI values ranging from 6.00-126.86). DHLC-1 and DHLC-2 demonstrated the greatest selectivity for the MCF-7 cells (with SI of 121 and 126.86 respectively) over the MCF-12A cells. This reveals that, overall, the derivatives display greatly improved selectivity for breast cancer over non-tumorigenic mammary epithelial cells, with between 100-fold and 12 000-fold higher SI values. The improved docking scores were recorded for all the 13-amino dehydrocostus lactone derivatives for the enzymes analyzed. Compounds DHLC-4, and DHLC-3 recorded higher docking scores of -7.33 and -5.97 Kca/mol respectively, compared to the parent structure, dehydrocostus lactone (-5.34 Kca/mol) for protein kinase (PKC) theta (1XJD) and -6.22 and -5.88 Kca/mol, respectively for protein kinase iota (1RZR). The compounds further showed promising predicted adsorption, distribution, metabolisms and excretion (ADME) properties. Predicting the ADME properties of these derivatives is of importance in evaluating their drug-likeness, which could in turn be developed into potential drug candidates.

Synthesis of 2-(N-cyclicamino)quinoline combined with methyl (E)-3-(2/3/4-aminophenyl)acrylates as potential antiparasitic agents.

A rationally designed series of 2-(N-cyclicamino)quinolines coupled with methyl (E)-3-(2/3/4-aminophenyl)acrylates was synthesized and subjected to in vitro screening bioassays for potential antiplasmodial and antitrypanosomal activities against a chloroquine-sensitive (3D7) strain of Plasmodium falciparum and nagana Trypanosoma brucei brucei 427, respectively. Substituent effects on activity were evaluated; meta-acrylate 24 and the ortho-acrylate 29 exhibited the highest antiplasmodial (IC50 = 1.4 µM) and antitrypanosomal (IC50 = 10.4 µM) activities, respectively. The activity against HeLa cells showed that the synthesized analogs are not cytotoxic at the maximum tested concentration. The ADME (absorption, distribution, metabolism, and excretion) drug-like properties of the synthesized compounds were predicted through the SwissADME software.

Easily accessed nitroquinolones exhibiting potent and selective anti-tubercular activity.

Nitro based DprE1 inhibitors exemplified by benzothiazinones have been reported to elicit potent anti-tubercular activity. Poor PK properties associated with benzothiazinones have inspired the discovery of alternative nitro based DprE1 inhibitors. Quinolone based antibiotics on the other hand have good PK properties. The potent anti-tubercular activity of nitro compounds and the good PK properties of the quinolones have elicited an interest in us to construct a new class of nitro containing compounds around the quinolone scaffold with the aim of identifying novel DprE1 inhibitors with potent anti-tubercular activity. Thus, we report herein the anti-tubercular activity of novel 6-nitroquinolone-3-carboxamide derivatives achieved using less than five cheap synthetic transformations. Among the 23 target compounds evaluated for anti-tubercular activity, 12 were active against Mtb─ exhibiting activity in the range of <0.244-31.865 µM. Compound 25 having a molecular weight of 399 Da and ClogP value of 2.7 is the most active (MIC90: <0.244 µM) in this series. The SAR analyses suggest that anti-tubercular activity was influenced by substituents at position N-1 (R2) and C-3 (R3) of the quinolone ring. The activity data suggest that the nature of R3 has a stronger influence on the SAR compared to R2; with a fluorobenzyl and chlorobenzyl moiety at R2 being the most favoured when R3 is an aliphatic amine. Docking study confirms that compound 25 binds to the same hydrophobic pocket as does TCA1, and other nitro based DprE1 inhibitors, with its nitro group in close proximity with Cys387 residue.