Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities.

A series of quinazolin-4(3H)-one derivatives was designed through scaffold-hopping strategy and synthesized as novel multifunctional anti-AD agents demonstrating both cholinesterase inhibition and anti-inflammatory activities. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated, and the enzyme kinetics study as well as detailed binding mode via molecular docking were performed for selected compounds. MR2938 (B12) displayed promising AChE inhibitory activity with an IC50 value of 5.04 µM and suppressed NO production obviously (IC50 = 3.29 µM). Besides, it was able to decrease the mRNA levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-6 and CCL2 at 1.25 µM. Further mechanism study suggested that MR2938 suppressed the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. All these results indicate that MR2938 is a good starting point to develop multifunctional anti-AD lead compounds.

Semi-Synthesis and Biological Evaluation of 25(R)-26-Acetoxy-3ß,5α-Dihydroxycholest-6-One.

Previously, we identified a series of steroids (1-6) that showed potent anti-virus activities against respiratory syncytial virus (RSV), with IC50 values ranging from 3.23 to 0.19 µM. In this work, we first semi-synthesized and characterized the single isomer of 5, 25(R)-26-acetoxy-3ß,5α-dihydroxycholest-6-one, named as (25R)-5, in seven steps from a commercially available compound diosgenin (7), with a total yield of 2.8%. Unfortunately, compound (25R)-5 and the intermediates only showed slight inhibitions against RSV replication at the concentration of 10 µM, but they possessed potent cytotoxicity activities against human bladder cancer 5637 (HTB-9) and hepatic cancer HepG2, with IC50 values ranging from 3.0 to 15.5 µM without any impression of normal liver cell proliferation at 20 µM. Among them, the target compound (25R)-5 possessed cytotoxicity activities against 5637 (HTB-9) and HepG2 with IC50 values of 4.8 µM and 15.5 µM, respectively. Further studies indicated that compound (25R)-5 inhibited cancer cell proliferation through inducing early and late-stage apoptosis. Collectively, we have semi-synthesized, characterized and biologically evaluated the 25R-isomer of compound 5; the biological results suggested that compound (25R)-5 could be a good lead for further anti-cancer studies, especially for anti-human liver cancer.

Discovery of Marine Natural Products as Promising Antibiotics against Pseudomonas aeruginosa.

Pseudomonas aeruginosa, one of the most intractable Gram-negative bacteria, has become a public health threat due to its outer polysaccharide layer, efflux transporter system, and high level of biofilm formation, all of which contribute to multi-drug resistance. Even though it is a pathogen of the highest concern, the status of the antibiotic development pipeline is unsatisfactory. In this review, we summarize marine natural products (MNPs) isolated from marine plants, animals, and microorganisms which possess unique structures and promising antibiotic activities against P. aeruginosa. In the last decade, nearly 80 such MNPs, ranging from polyketides to alkaloids, peptides, and terpenoids, have been discovered. Representative compounds exhibited impressive in vitro anti-P. aeruginosa activities with MIC values in the single-digit nanomolar range and in vivo efficacy in infectious mouse models. For some of the compounds, the preliminary structure-activity-relationship (SAR) and anti-bacterial mechanisms of selected compounds were introduced. Compounds that can disrupt biofilm formation or membrane integrity displayed potent inhibition of multi-resistant clinical P. aeruginosa isolates and could be considered as lead compounds for future development. Challenges on how to translate hits into useful candidates for clinical development are also proposed and discussed.