Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors.

FMS-like tyrosine kinase 3 (FLT3) is an ideal drug target for the treatment of acute myeloid leukemia (AML). Although several FLT3 inhibitors have been approved or evaluated in clinical trials, selectivity over c-Kit kinase and FLT3 WT remains a major challenge. Herein, we report a series of 4-(2-fluorophenoxy)pyridine derivatives with potent inhibitory activities against FLT3 internal tandem duplication (FLT3-ITD).

Nickel-Catalyzed Rearranged Alkenylation of 2-Arylaziridines with Aryl Alkenes to Access Allylamines.

The transition-metal-catalyzed ring-opening functionalization of aziridines presents a promising approach for synthesizing structurally complex amines. However, the rearranged functionalization of aziridines poses significant challenges. Herein, we report the first rearranged alkenylation of aziridines with aryl alkenes via Ni-Brønsted acid co-catalysis, leading to the rapid synthesis of a diverse array of allylamines with yields reaching up to 91%.

Discovery of highly potent mTOR inhibitors aimed at suppressing the progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological malignancy with complex etiology; however, current standard chemotherapy regimens for AML show limited efficacy and unsatisfactory tolerability. Herein, a novel class of trisubstituted triazine mTOR inhibitors was designed and synthesized, and the optimal compound, HPT-11, exhibited potent inhibition against mTOR kinase and Molm-13 cell proliferation activities with inhibitory IC values of 0.7 and 12 nM, respectively.

Access to Chiral Dihydro-1,4-Benzoxazine-2-Carboxylates through NHC-Catalyzed Dynamic Kinetic Resolution.

A chiral carbene-catalyzed dynamic kinetic resolution for the facile synthesis of enantioenriched dihydro-1,4-benzoxazine-2-carboxylates is disclosed. The reaction conditions are mild, and a diversity of substituents are well-tolerated in this transformation. In addition, our methodology also provides an efficient strategy for building chiral chromane-2-carboxylate and 2,3-dihydro-1,4-benzodioxane-2-carboxylate.

Discovery of pyridine-based derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia.

FMS-like tyrosine receptor kinase 3 (FLT3) mutations, the most common genetic alterations found in acute myeloid leukemia (AML) patients, have been pursued as an ideal drug discovery target for the AML therapy. Taking compound 2 as lead, a series of pyridine derivatives bearing 1,2,3-triazole moiety were rationally designed and synthesized. The bioassays confirmed that these derivatives exerted potent antileukemia effects, and compound 12y was found to be the most potent one.

Synthesis of Novel Chromene Derivatives Bearing Hydrazide/Thiazol/Oxazol/Oxime Moieties as Potential Antifungal Agents.

Four series of novel hydrazide/thiazol/oxazol/oxime ester hybrids of chromene derivatives were designed and synthesized to explore natural-product-based fungicide candidates. Preliminary antifungal activity assay results demonstrated that hydrazide-chromene and thiazol-chromene derivatives exhibited excellent and broad-spectrum inhibitory activity against ten phytopathogenic fungi. Among them, six compounds , , , , , and displayed the most remarkable antifungal effects.

Design and synthesis of some novel structurally diverse thiochroman derivatives as fungicides against phytopathogenic fungi.

Background: Plant diseases infected by pathogenic fungi have a devastating effect on global agricultural and food industry yields. The development of novel, environmentally friendly, and efficient fungicides is an important technique for preventing and combatting phytopathogenic fungi.

Results: Herein, 99 thiochroman-based derivatives containing hydroxyl, sulfoxide, sulfone, carbonyl, double bond, amino, imine, oxime, oxime ester, and amide moieties were synthesized.

Redox-Neutral Coupling of Allyl Alcohols with Trifluoromethyl Ketones via Synergistic Ni-Ti Bimetallic Catalysis.

A redox-neutral coupling of allyl alcohols with trifluoromethyl ketones has been developed via Ni-Ti bimetallic catalysis. This innovative method allows for the efficient synthesis of various β-tertiary trifluoromethyl alcohol-substituted ketones with yields of up to 98%. The reaction is scalable and compatible with a wide range of substrates, including complex bioactive molecules.

Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and characterisation.

The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds.

Development of a hydroxypropyl methyl cellulose/polyacrylic acid interpolymer complex formulated buccal mucosa adhesive film to facilitate the delivery of insulin for diabetes treatment.

Buccal mucosa administration is a promising method for insulin (INS) delivery with good compliance. However, buccal mucosa delivery systems still face challenges of long-term mucosal adhesion, sustained drug release, and mucosal drug penetration. To address these issues, a double-layer film consisting of a hydroxypropyl methylcellulose/polyacrylic acid interpolymer complex (IPC)-formulated mucoadhesive layer and an ethylcellulose (EC)-formulated waterproof backing layer (IPC/EC film) was designed.

Design and Synthesis of Novel Phthalide Derivatives containing 1,3,4-Oxadiazole/1,2,4-Triazole Units as Potential Antifungal Agents.

Four series of novel 1,3,4-oxadiazole/1,2,4-triazole hybrids of phthalide derivatives were designed and synthesized to search for novel potential antifungal agents. Preliminary antifungal activity assay results showed that compounds 4 a, 4 b, 4 m, 5 b, 5 f, 5 h, and 7 h exhibited moderate to excellent inhibitory activity against some phytopathogenic fungi. Among them, compound 5 b displayed the most outstanding antifungal effects against V.

Integrated investigation and experimental validation of PPARG as an oncogenic driver: implications for prognostic assessment and therapeutic targeting in hepatocellular carcinoma.

Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases.

Aerobic Dehydrogenative Aromatization in the Preparation of 4-Aminoquinoline Derivatives by Synergistic Pd/Cu Catalysis.

The 4-aminoquinoline moiety is widely present in various bioactive compounds and marketed drugs, while the preparation of this target structure relies heavily on the amination of 4-chloroquinolines. Herein, an atom and step economic procedure was developed based on an aerobic dehydrogenative aromatization strategy. Unlike the well-known palladium-catalyzed dehydrogenative aromatization of cyclohexanones with amines, synergistic Pd/Cu catalysis is crucial for 2,3-dihydroquinolin-4(1)-one type of substrates.

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold.

Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3K inhibitors.

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3K and a panel of PI3K-addicted cancer cells. Among them, compound was identified as a PI3K inhibitor with nanomolar potency as well as acceptable antiproliferative activity.

Design, synthesis and biological evaluation of cajanonic acid A analogues as potent PPAR γ antagonists.

Peroxisome proliferator-activated receptor γ (PPAR γ) antagonists are a key instrument of insulin sensitizers since they have the ability to sensitize insulin and can avoid adverse reactions caused by receptor agonist. In this paper, two series of 28 novel Cajanonic acid A (CAA) derivatives were designed and synthesized. The biological activity showed that a novel CAA derivative 9f was identified as a potential PPAR γ antagonist by medicinal chemistry efforts.

Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies.

Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy.

Synthesis and biological evaluation of cajanonic acid A derivatives as potential PPARγ antagonists.

Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities.

Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents.

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.

Design, synthesis and bioevaluation of novel substituted triazines as potential dual PI3K/mTOR inhibitors.

A series of novel substituted triazines bearing a benzimidazole scaffold were designed and synthesized based on the structures of known anti-cancer agents, namely gedatolisib and alpelisib. All the target compounds were screened for inhibitory activity against PI3Kα and mTOR kinases. Notably, most analogs exhibited IC in the nanomolar range.

Pharmacokinetics, Tissue Distribution, and Excretion Study of Cajanonic Acid A in Rats by UPLC-MS/MS.

Cajanonic acid A (CAA), a prenylated stilbene derivative extracted from the leaves of pigeon pea (), has been reported to possess inhibitory activity on the peroxisome proliferator-activated receptor gamma (PPAR) and protein tyrosine phosphatase 1B (PTP1B). Its hypoglycemic activity in rats is comparable to that of the approved antidiabetic agent rosiglitazone. Therefore, CAA is a potential candidate for the treatment of type 2 diabetes and a lead compound for the discovery of novel hypoglycemic drugs.

Novel berberine-based derivatives with potent hypoglycemic activity.

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.

Munronin O, a potential activator for plant resistance.

A series of limonoids (1-8) were isolated from the whole plant of Munronia henryi and antiviral activities of the compounds were evaluated. The bioassay results demonstrated that Munronin O (1) showed remarkable protective activity and compounds 7 and 8 showed significant inactivating, protective, and curative activities against tobacco mosaic virus (TMV). With a 50% effective concentration (EC) value of 91.

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

Background And Purpose: Glucagon-like peptide-1 (GLP-1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP-1 related antidiabetic mechanisms in vitro and in vivo.

Experimental Approach: The therapeutic effects of DKS26 were investigated in streptozotocin (STZ)-induced and db/db diabetic mouse models.

Protective effects of Semiaquilegia adoxoides n-butanol extract against hydrogen peroxide-induced oxidative stress in human lens epithelial cells.

Context Hydrogen peroxide (H2O2)-induced damage in the lens epithelium leads to cell death and cataract. Semiaquilegia adoxoides (DC.) Makino (Ranunculaceae), a folk medicine of Hmong (an ethnic group of China), has been traditionally used to treat cataract; however, the underlying molecular mechanism is yet to be uncovered.