6291-74-3Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ
Li, Zheng,Zhou, Zongtao,Deng, Fengjian,Li, Yuyi,Zhang, Danjun,Zhang, Luyong
supporting information, p. 267 - 276 (2018/10/15)
The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes.
Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors
Luan, Shenglin,Ge, Qi,Chen, Yedong,Dai, Mingyang,Yang, Jinyu,Li, Kun,Liu, Dan,Zhao, Linxiang
supporting information, p. 1943 - 1948 (2017/04/07)
Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110?nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.
Novel Carboline Derivatives as Potent Antifungal Lead Compounds: Design, Synthesis, and Biological Evaluation
Wang, Shengzheng,Wang, Yan,Liu, Wei,Liu, Na,Zhang, Yongqiang,Dong, Guoqiang,Liu, Yang,Li, Zhengang,He, Xiaomeng,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
, p. 506 - 511 (2014/06/09)
A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against both fluconazole-sensitive and -resistant Candida albicans cells and had potent inhibition activity against Candida albicans biofilm formation and hyphal growth. Moreover, C38 showed good synergistic antifungal activity in combination with fluconazole (FLC) against FLC-resistant Candida species. Preliminary mechanism studies revealed that C38 might act by inhibiting the synthesis of fungal cell wall.
The synthesis and preliminary pharmacological evaluation of a series of substituted 4-phenoxypropyl analogues of the atypical antipsychotic clozapine
Capuano, Ben,Crosby, Ian T.,McRobb, Fiona M.,Podloucka, Anna,Taylor, David A.,Vom, Amelia,Yuriev, Elizabeth
experimental part, p. 116 - 124 (2010/05/18)
Herein we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted 4′-phenoxypropyl tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. The lead comp
Improved model of lanosterol 14α-demethylase by ligand-supported homology modeling: Validation by virtual screening and azole optimization
Sheng, Chunquan,Wang, Wenya,Che, Xiaoying,Dong, Guoqiang,Wang, Shengzheng,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
experimental part, p. 390 - 397 (2010/11/18)
Lanosterol 14α-demethylase (CYP51) is an important target for antifungal drugs. An improved three-dimensional model of CYP51 from Candida albicans (CACYP51) was constructed by ligand-supported homology modeling and molecular dynamics simulations. The accuracy of the constructed model was evaluated by its performance in a small-scale virtual screen. The results show that known CYP51 inhibitors were efficiently discriminated by the model, and it performed better than our previous CACYP51 model. The active site of CACYP51 was characterized by multiple copy simultaneous search (MCSS) calculations. On the basis of the MCSS results, a series of novel azoles were designed and synthesized, and they showed good in vitro antifungal activity with a broad spectrum. The MIC80 value of four of these compounds against C. albicans is 0.001 μgmL-1, indicating that they are promising leads for the discovery of novel antifungal agents.
New azoles with potent antifungal activity: Design, synthesis and molecular docking
Che, Xiaoying,Sheng, Chunquan,Wang, Wenya,Cao, Yongbing,Xu, Yulan,Ji, Haitao,Dong, Guoqiang,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
scheme or table, p. 4218 - 4226 (2009/12/09)
In response to the urgent need for novel antifungal agents with improved activity and broader spectrum, computer modeling was used to rational design novel antifungal azoles. On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles with substituted-phenoxypropyl piperazine side chains were rational designed and synthesized. In vitro antifungal activity assay indicates that the new azoles show good activity against most of the tested pathogenic fungi. Interestingly, the designed compounds are also active against an azole-resistant clinical strain. Compared to fluconazole and itraconazole, several compounds (such as 12i, 12j and 12n) show higher antifungal activity and broader spectrum, which are promising leads for the development of novel antifungal agents.
Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials
Jensen,Ager,Bliss,Canfield,Kotecka,Rieckmann,Terpinski,Jacobus
, p. 3925 - 3931 (2007/10/03)
A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.
Selectivity in alkylation of phenols with 1-bromo-3-chloropropane using phase-transfer catalysis
Reinholz,Becker,Hagenbruch,Schafer,Schmitt
, p. 1069 - 1071 (2007/10/02)
The use of various phase-transfer catalysts in the alkylation of phenol and substituted phenols with 1-bromo-3-chloropropane was investigated. When a quarternary ammonium salt of the general formula R'4N+ X-, where R' = alkyl with a minimum chain length of 4 was used, a mixture of 1-aryloxy-3-chloropropane and 1-aryloxy-3-bromopropane resulted. The effect of counterion, added potassium bromide, and catalysts other than quarternary ammonium salts were assessed for the halopropylation of 2,5-dimethylphenol.
