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Abstract
A pyrimidine moiety exhibiting a wide range of pharmacological activities has been employed in the design of privileged structures in medicinal chemistry. To prepare libraries of novel heterocyclic compounds with potential biological activities, a series of novel 2-(pyridin-2-yl) pyrimidine derivatives were designed, synthesized and their biological activities were evaluated against immortalized rat hepatic stellate cells (HSC-T6). Fourteen compounds were found to present better anti-fibrotic activities than Pirfenidone and Bipy55′DC. Among them, compounds ethyl 6-(5-(p-tolylcarbamoyl)pyrimidin-2-yl)nicotinate (12m) and ethyl 6-(5-((3,4-difluorophenyl)carbamoyl)pyrimidin-2-yl)nicotinate (12q) show the best activities with IC50 values of 45.69 μM and 45.81 μM, respectively. Furthermore, the study of anti-fibrosis activity was evaluated by Picro-Sirius red staining, hydroxyproline assay and ELISA detection of Collagen type I alpha 1 (COL1A1) protein expression. Our study showed that compounds 12m and 12q effectively inhibited the expression of collagen, and the content of hydroxyproline in cell culture medium in vitro, indicating that compounds 12m and 12q might be developed the novel anti-fibrotic drugs.
Highlights
Construction of novel heterocyclic compound libraries with potential biological activities is an important component of medicinal chemistry and chemical biology [1]
63% in a liver fibrosis model [12]; N2,N4 -bis(2-methoxyethyl)pyridine-2,4-dicarboxamide (HOE-077), which is a prodrug of pyridine-2,4-dicarboxylic acid (24PDC), can inhibit collagen synthesis in rat and dog models by inactivating hepatic stellate cells that are mainly responsible for collagen synthesis in liver fibrosis [13,14]; Ethyl 3,4-dihydroxybenzoate and S4682 were effective in inhibiting collagen synthesis in keloid fibroblasts or the CCl4 model of chronic hepatic injury, by inhibition of collagen prolyl-4-hydroxylase (CP4H) [14,15]; 2-(benzo[d][1,3]dioxol-5-yl)thiazole (CW209292)
The key intermediate 5 was obtained by a convenient four-step procedure in undertaken to yield 2; compound 2 was oxidated with 3-chloroperoxybenzoic acid to moderate yields and the synthetic route was depicted in Scheme 1: First, esterification of nicotinic afford pyridine N-Oxides 3; a nucleophilic substitution of the ortho-position of pyridine N-Oxides acid was undertaken to yield 2; compound 2 was oxidated with 3-chloroperoxybenzoic acid 3 with trimethylsilyl cyanide (TMSCN) was conducted to generate 4 [24]; compound 4 was to afford pyridine N-Oxides 3; a nucleophilic substitution of the ortho-position of reacted with Na and NH4 Cl in EtOH solution to get compound 5 [25]
Summary
Construction of novel heterocyclic compound libraries with potential biological activities is an important component of medicinal chemistry and chemical biology [1]. The pyrimidine moiety has been considered as a privileged structure in medicinal chemistry [2] and the compounds containing pyrimidine as the core are reported to exhibit diverse types of biological and pharmaceutical activities. Displays anti-fibrotic activity in rats with dimethylnitrosamine (DMN)-induced hepatic fibrosis by Molecules 2020, 25, 5226; doi:10.3390/molecules25225226 www.mdpi.com/journal/molecules. Molecules 2020, 25, x FOR PEER REVIEW blocking the mRNA expression of transforming growth factor-β1 (TGF-β1) in hepatic stellate cells [16];. TGF-β in thioacetamide (TAA)-induced hepatic fibrogenesis [17]. All of those small molecules contain in thioacetamide (TAA)-induced hepatic fibrogenesis [17] All of those small molecules contain the the structure fragment
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