Synthesis and evaluation of ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives as anti-inflammatory agents
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ORIGINAL ARTICLE
Synthesis and evaluation of ursolic acid‑based 1,2,4‑triazolo[1,5‑a] pyrimidines derivatives as anti‑inflammatory agents Tian‑Yi Zhang1 · Chun‑Shi Li2 · Ping Li1 · Xue‑Qian Bai1 · Shu‑Ying Guo1 · Ying Jin1 · Sheng‑Jun Piao3 Received: 4 September 2020 / Accepted: 29 October 2020 © Springer Nature Switzerland AG 2020
Abstract Here, two series of novel ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives were synthesized and screened for their anti-inflammatory activity by evaluating their inhibition effect of using LPS-induced inflammatory response in RAW 264.7 macrophages in vitro; the effects of different concentrations of the compounds on the secretion of nitric oxide (NO) and inflammatory cytokines including TNF-α and IL-6 were evaluated. Their toxicity was also assessed in vitro. Results showed that the most prominent compound 3 could significantly decrease production of the above inflammatory factors. Docking study was performed for the representative compounds 3, UA, and Celecoxib to explain their interaction with cyclooxygenase-2 (COX-2) receptor active site. In vitro enzyme study implied that compound 3 exerted its anti-inflammatory activity through COX-2 inhibition. Keywords Ursolic acid · Anti-inflammatory activity · Molecular modeling · COX-2 inhibition
Introduction The inflammatory process is an immune response to a perturbation of the homeostatic equilibrium of the organism, whether endogenous or exogenous [1–3]. Inflammation can lead to further tissue damage that can eventually Tian-Yi Zhang and Chun-Shi Li have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10154-7) contains supplementary material, which is available to authorized users. * Tian‑Yi Zhang [email protected] * Ying Jin [email protected] * Sheng‑Jun Piao [email protected] 1
Jilin Medical University, Jilin 132013, Jilin Province, People’s Republic of China
2
The Third People’s Hospital of Dalian, Dalian 116000, Liaoning Province, People’s Republic of China
3
Department of General Surgery, Affiliated Hospital of Yanbian University, Yanji 133000, Jilin Province, People’s Republic of China
contribute to the pathogenesis of chronic inflammatory and autoimmune diseases such as rheumatoid arthritis [4], cardiovascular diseases [5], CNS neurological disorders [6], and ulcerative colitis [7]. Management of inflammatory disorders involves the use of therapeutic agents for relieving pain and reducing inflammation, either decreasing or neutralizing the levels of pro-inflammatory mediators or inhibiting the recruitment of leukocytes and their activation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are still widely used in clinical applications today. However, they usually cause unexpected side effects, such as peptic ulcers, bleeding, mucosal lesions, and nephrotoxicity [8, 9]. Traditional NSAIDs exhibit pharmacological action through the inhibition of cyclooxygenase (COX) activity in vivo and the reducti
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