Synthesis, Tautomeric Behavior, and Biological Activity of 6-Unsubstituted 2-Aryl-1,4-dihydropyrimidines and 4-Unsubstituted 2-Aryl-1,6-dihydropyrimidines
Abstract
Dihydropyrimidines (DPs) show a wide range of biological activities for medicinal applications. Among DP derivatives, 2-aryl-DPs have been reported to show remarkable pharmacological properties. In this work, 6-unsubstituted, N-unsubstituted 2-aryl-1,4-DP and its 1,6-DP tautomer were synthesized using a Pd2dba3/(2-furyl)3P-catalyzed, CuCl-mediated 2-arylation and a deprotection reaction. The sequential reactions give twenty types of the 1,4-DP and the 1,6-DP tautomers in high yields. To clarify the effects of substituents on their tautomeric behavior, 1H-NMR analysis of a mixture of the tautomers was performed. The analysis revealed that not only the electronic properties of substituents at the 2-position of 1,6-DP but also the electronic properties of substituents at the 4-position of 1,4-DP affect the stability of 1,4-DP and 1,6-DP. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Five compounds showed relatively high inhibitory activity, and their IC50 values were 1.7–3.9 μM. The analysis indicates that the 2-aryl group with a para-substituent and the cyclohexyl group are related to the biological activity.
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BibTeX
@article{nishimura2026synthesis,
title = {{Synthesis, Tautomeric Behavior, and Biological Activity of 6-Unsubstituted 2-Aryl-1,4-dihydropyrimidines and 4-Unsubstituted 2-Aryl-1,6-dihydropyrimidines}},
author = {Yoshio Nishimura and Keito Taira and Yusuke Yamamoto and Hidetomo Kikuchi and Rie Arai and Yuki Toguchi and Bo Yuan and Katsuyoshi Sunaga},
journal = {Chemical and Pharmaceutical Bulletin},
year = {2026},
month = sep,
doi = {10.1248/cpb.c26-00391},
url = {https://www.jstage.jst.go.jp/article/cpb/74/9/74_c26-00391/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Synthesis, Tautomeric Behavior, and Biological Activity of 6-Unsubstituted 2-Aryl-1,4-dihydropyrimidines and 4-Unsubstituted 2-Aryl-1,6-dihydropyrimidines
AU - Yoshio Nishimura
AU - Keito Taira
AU - Yusuke Yamamoto
AU - Hidetomo Kikuchi
AU - Rie Arai
AU - Yuki Toguchi
AU - Bo Yuan
AU - Katsuyoshi Sunaga
PY - 2026
DA - 2026/09/25
JO - Chemical and Pharmaceutical Bulletin
DO - 10.1248/cpb.c26-00391
UR - https://www.jstage.jst.go.jp/article/cpb/74/9/74_c26-00391/_article
AB - Dihydropyrimidines (DPs) show a wide range of biological activities for medicinal applications. Among DP derivatives, 2-aryl-DPs have been reported to show remarkable pharmacological properties. In this work, 6-unsubstituted, N-unsubstituted 2-aryl-1,4-DP and its 1,6-DP tautomer were synthesized using a Pd2dba3/(2-furyl)3P-catalyzed, CuCl-mediated 2-arylation and a deprotection reaction. The sequential reactions give twenty types of the 1,4-DP and the 1,6-DP tautomers in high yields. To clarify the effects of substituents on their tautomeric behavior, 1H-NMR analysis of a mixture of the tautomers was performed. The analysis revealed that not only the electronic properties of substituents at the 2-position of 1,6-DP but also the electronic properties of substituents at the 4-position of 1,4-DP affect the stability of 1,4-DP and 1,6-DP. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Five compounds showed relatively high inhibitory activity, and their IC50 values were 1.7–3.9 μM. The analysis indicates that the 2-aryl group with a para-substituent and the cyclohexyl group are related to the biological activity.
SN - 1347-5223
SN - 0009-2363
ER -