Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC 50 = 0.30 μM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R 1 ) and hydrophobic interactions of phenyl moiety (R 3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolonestype PL inhibitors for biomedical applications.

After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CL pro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1018 compounds has potent inhibitory activity against SARS-CoV-2 3CL pro with the IC 50 value of 4.78 ± 1.03 μM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CL pro . Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CL pro . Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.

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Bis(indolyl)methanes were synthesized by a green protocol. Primary structure–activity relationship analysis showed that the bisindolyl structure is essential for CES2 inhibition.

Introduction: Carboxyalkyl flavonoids derivatives are considered as effective inhibitors in reducing post-prandial hyperglycaemia. Methods: Combined with Density Functional Theory (DFT) and the theory of Atoms in Molecules (AIM), molecular docking and charge density analysis are carried out to understand the molecular flexibility, charge density distribution and the electrostatic properties of these carboxyalkyl derivatives. Results: Results show that the electron density of the chemical bond C14-O17 on B ring of molecule II increases while O17-H18 decreases at the active site, suggesting the existence of weak noncovalent interactions, most prominent of which are H-bonding and electrostatic interaction. When hydroxyl groups are introduced, the highest positive electrostatic potentials are distributed near the B ring hydroxyl hydrogen atom and the carboxyl hydrogen atom on the A ring. It was reported that quercetin has a considerably inhibitory activity to S. cerevisiae α-glucosidase, from the binding affinities, it is suggested that the position and number of hydroxyl groups on the B and C rings are also pivotal to the hypoglycemic activity when the long carboxyalkyl group is introduced into the A ring. Conclusion: It is concluded that the presence of three well-defined zones in the structure, both hydrophobicity alkyl, hydrophilicity carboxyl and hydroxyl groups are necessary.