61098-39-3Relevant academic research and scientific papers
Development of Pyrazolopyrimidine Anti- Wolbachia Agents for the Treatment of Filariasis
McGillan, Paul,Berry, Neil G.,Nixon, Gemma L.,Leung, Suet C.,Webborn, Peter J. H.,Wenlock, Mark C.,Kavanagh, Stefan,Cassidy, Andrew,Clare, Rachel H.,Cook, Darren A.,Johnston, Kelly L.,Ford, Louise,Ward, Stephen A.,Taylor, Mark J.,Hong, W. David,O'Neill, Paul M.
, p. 1421 - 1426 (2021/09/11)
Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.
Picolinamide compound and preparation method and application thereof
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Paragraph 0073; 0075; 0081-0085; 0106; 0108; 0110; 0121, (2020/08/02)
The invention discloses a picolinamide compound. The structural general formulas of the picolinamide compound are shown as formulas (I) and (II). The invention also discloses a preparation method of the picolinamide compound and application of the picolinamide compound in preparation of anti-tumor drugs. The picolinamide compound can effectively inhibit a variety of tumor cells, including human breast cancer cells, human lung cancer cells, human liver cancer cells and the like, has good anti-tumor active substances and can be used for preparing the anti-tumor drugs.
Design, synthesis and antitumor evaluation of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives as potential c-Met inhibitors
Luo, Guolin,Ma, Yanxia,Liang, Xintong,Xie, Guoquan,Luo, Yingqi,Zha, Dailong,Wang, Sheng,Yu, Lihong,Zheng, Xuehua,Wu, Wenhao,Zhang, Chao
, (2020/10/18)
A series of novel 5-methylpyrazolo[1,5-a]pyrimidine derivatives (10a–10x) were designed, synthesized, and evaluated for their in vitro inhibitory activities against c-Met kinase and antiproliferative activities against the SH-SY5Y, MDA-MB-231, A549, and HepG2 cell lines. Most of the compounds remarkably inhibited c-Met kinase and showed moderate to good cytotoxicity and selectivity toward the four cancer cell lines. Among them, compounds 10b and 10f were the two most potent selective c-Met inhibitors with half-maximal inhibitory concentration (IC50) values of 5.17 ± 0.48 nM and 5.62 ± 0.78 nM, respectively, and suppression abilities comparable with the positive control cabozantinib. Cell proliferation assay further demonstrated that the two most promising compounds 10a and 10b also showed good cytotoxicity and selectivity toward MDA-MB-231 cells, with IC50 values of 26.67 ± 2.56 μM and 26.83 ± 2.41 μM, respectively. Compounds 10f and 10g showed cytotoxicity and selectivity toward A549 cells, with IC50 values of 20.20 ± 2.04 μM and 21.65 ± 1.58 μM, respectively. All antiproliferative activities were within the range of those of cabozantinib. Notably, these compounds presented relatively low hepatotoxicity compared with reference drugs. Moreover, the preliminary structure–activity relationship and docking studies revealed that replacement of a nitrogen-containing heterocycle on the R2 (block A) group might improve the c-Met kinase inhibitory and antiproliferative effects in MDA-MB-231 cells, whereas displacement by a substituted benzene ring, especially for the p-fluorophenyl or 4-fluoro-3-methoxyphenyl moiety, on the R2 group enhanced cytotoxicity toward A549 cells. Together, these results suggest that 10b and 10f are promising compounds and provide a basis for their development as new antitumor agents.
Synthesis and antifungal properties of certain 7 alkylaminopyrazolo[1,5 a]pyrimidines
Novinson,Robins,Matthews
, p. 296 - 299 (2007/10/06)
A series of 7-alkylaminopyrazolo[1,5-α]pyrimidines (5-25) and one 7-alkylthiopyrazolo[1,5-α]pyrimidine (4) were synthesized from the corresponding 7-chloro precursors 3, which were prepared in turn from the 7-hydroxy analogues 2, obtained via condensation of 3-aminopyrazoles with acetoacetate esters, malonate esters, or acetylenedicarboxylate ester. Compounds 4-25 were found to inhibit Trichophyton mentagrophytes (in vitro). The degree of inhibition increased with increasing 7-alkylamino chain length up to C8 units and then began to decrease with longer chain lengths. Unsaturated chains were more fungitoxic than saturated chains, 5-methyl-7-oleylaminopyrazolo[1,5-α]pyrimidine [22, R7 = NH(CH2)8 CH=CH(CH2)7CH3] being 4 times more inhibitory and 16 times more fungicidal (against T. mentagrophytes) than 5-methyl-7-n octylaminopyrazolo[1,5-α]pyrimidine [11,R7=NH(CH2)7CH3]. Although 11 and 22 appeared to have some efficacy as topical antifungal agents, when applied to T. mentagrophytes infections in vivo, both caused irritation (of abraded and unabraded guinea pig skin) as did compound 4 (R5=Me; R7=SC8H17).
