Anticandidal formyl phloroglucinol meroterpenoids: Biomimetic synthesis and in vitro evaluation.

Inspired by the diversity-oriented synthesis, some novel formyl phloroglucinol meroterpenoids were synthesized via biomimetic synthesis using essential oils. Eight of them were demonstrated with good in vitro fungicidal activity against Candida albicans and C. glabrata. Compound c2 showed the best anticandidal ability that was powerfully comparable to fluconazole when testing against several strains in vitro. The antibiofilm activity was also found for the c2 treating group which was evidenced to block the hyphal elongation and filamentation of C. albicans. Therefore, compound c2 is a promising candidate for further antifungal-based structure modification.

Novel Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo.

Triazoles have demonstrated significant efficacy in the treatment of fungal infections. However, increasing drug resistance is a growing concern that negatively impacts their effectiveness. By designing a well-crafted side chain, triazoles can be endowed with advantages, like higher potency and the ability to overcome drug resistance. This highlights the diverse interactions between side chains and CYP51. To explore novel triazole antifungal agents, we synthesized three series of fluconazole-core compounds and focused on optimizing the chain based on molecule docking and in vitro results. The most potent S-F24 exhibited excellent broad-spectrum antifungal activity that was better or comparable to clinically used azoles. S-F24 maintained its potency even against multi-resistant Candida albicans. Additionally, S-F24 displayed a good safety profile with high selectivity, low hemolytic effects, and low tendency to induce resistance. Our findings collectively demonstrated that there was still a high potential for side-chain modification in the development of novel azoles.

Discovery of novel brain-penetrant GluN2B NMDAR antagonists via pharmacophore-merging strategy as anti-stroke therapeutic agents.

In this work, a novel structural series of brain-penetrant GluN2B NMDAR antagonists were designed, synthesized and biologically evaluated as anti-stroke therapeutic agents via merging the structures of NBP and known GluN2B ligands. Approximately half of them exhibited superior neuroprotective activity to NBP against NMDA-induced neurotoxicity in hippocampal neurons at 10 µM, and compound 45e and 45f exerted equipotent activity to ifenprodil, an approved GluN2B- selective NMDAR antagonist. In particular, 45e, with the most potent neuroprotective activity throughout this series, displayed dramatically enhanced activity (Ki = 3.26 nM) compared to ifenprodil (Ki = 14.80 nM) in Radioligand Competitive Binding Assay, and remarkable inhibition (IC50 = 79.32 nM) against GluN1/GluN2B receptor-mediated current in Patch Clamp Assay. Meanwhile, 45e and its enantiomers exhibited low inhibition rate against the current mediated by other investigated receptors at the concentration of 10 µM, indicating their favorable selectivity for GluN1/GluN2B. In the rat model of middle cerebral artery ischemia (MCAO), 45e exerted comparable therapeutic efficacy to ifenprodil at the same dosage. In addition to the attractive in vitro and in vivo potency, 45e displayed a favorable bioavailability (F = 63.37%) and an excellent brain exposure. In further repeated dose toxicity experiments, compound 45e demonstrated an acceptable safety profile. With the above merits, 45e is worthy of further functional investigation as a novel anti-stroke therapeutic agent.

Epicoccanes A-D, Four Oxidative Dimers of Pyrogallol Analogues from Epicoccum nigrum.

Epicoccanes A-D (1-4) are four novel metabolites of an endophytic fungus Epicoccum nigrum. Their distinct unprecedented structures are hypothesized as oxidative dimers of pyrogallol analogues. Compounds 1 and 2 possess a novel spirobicyclo[3.2.1]octane-6,1'-cyclopentane or -cyclohexane core skeleton. Compound 3 is of a unique cage-like pentacyclic system, which unusually contained three continuous spiro-carbons. Compound 4 is a highly rearranged dimer with five contiguous chiral centers. The absolute structures of 1 and 2 were deduced by electronic circular dichroism (ECD) calculations, and those of 3 and 4 were determined by X-ray crystallography. Compounds 1 and 4 showed potential antiliver fibrosis activity.

Design, synthesis, and evaluation of genipin derivatives for the treatment of Alzheimer's Disease.

Twenty-two novel genipin derivatives have been designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this series with IC50 value of 218 nm. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid ß-protein 1-42 (Aß1-42 ). Among them, 8a showed higher inhibition rate (%Inhibition = 22.29) than the positive reference Donepezil (%Inhibition = 17.65).

Design, synthesis chalcone derivatives as AdipoR agonist for type 2 diabetes.

Two structurally novel series of chalcone derivatives were designed and synthesized as potential agents against type 2 diabetes. As a result of the antidiabetic biological evaluation in streptozotocin (STZ)-induced type 2 diabetes animal model, 13e, 13g, and 19f showed more significant reduction in serum Glu, TG, TC levels by contrast to the positive control AdipoRon. In addition to upregulating the expression of AdipoR1 and AdipoR2, 13e and 19f treatment also increased expression of AMPK and PPAR-α. Taken together, these results suggested that 13e and 19f might be a promising compound for type 2 diabetes treatment.

Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate.

A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF-7, and HT-29 were evaluated. Compared with colchicine (1.04 × 10-2  µm), 17d and 17e exhibited outstanding activity on MCF-7 with IC50 values 0.26 × 10-2  µm and 0.89 × 10-3 µm in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate. In the MCF-7-xenograft mouse model that was treated with 17d and 17e by intraperitoneal injection, the tumor weight was decreased at same rate with tamoxifen, and relative tumor proliferation rates were 59.48% and 41.33%, while tamoxifen was 45.08% with a daily dose of 20 mg/kg, which were demonstrated potent in vivo efficacy.

Design, Synthesis and Pharmacological Evaluation of Novel Piperlongumine derivatives as Potential Antiplatelet Aggregation Candidate.

A series of novel piperlongumine derivatives (4a-i, 6a-i) were designed and synthesized. The inhibitory activities of platelet aggregation induced by ADP and AA in vitro have been evaluated by bron turbidimetry and liver microsomal incubated assay. The assay results show that compounds 4e and 6e exhibited remarkable potency to that of the positive control piplartine and aspirin.