Objective The present study aimed to investigate five triazole compounds as P2X7R inhibitors and evaluate their ability to reduce acute inflammation in vivo. Material The synthetic compounds were labeled 5e , 8h , 9i , 11 , and 12 . Treatment We administered 500 ng/kg triazole analogs in vivo, (1–10 µM) in vitro, and 1000 mg/kg for toxicological assays. Methods For this, we used in vitro experiments, such as platelet aggregation, in vivo experiments of paw edema and peritonitis in mice, and in silico experiments. Results The tested substances 5e , 8h , 9i , 11 , and 12 produced a significant reduction in paw edema. Molecules 5e , 8h , 9i , 11 , and 12 inhibited carrageenan-induced peritonitis. Substances 5e , 8h , 9i , 11 , and 12 showed an anticoagulant effect, and 5e at a concentration of 10 µM acted as a procoagulant. All derivatives, except for 11 , had pharmacokinetic, physicochemical, and toxicological properties suitable for substances that are candidates for new drugs. In addition, the ADMET risk assessment shows that derivatives 8h , 11 , 5e , and 9i have high pharmacological potential. Finally, docking tests indicated that the derivatives have binding energies comparable to the reference antagonist with a competitive inhibition profile. Conclusions Together, the results indicate that the molecules tested as antagonist drugs of P2X7R had anti-inflammatory action against the acute inflammatory response. Supplementary Information The online version contains supplementary material available at 10.1007/s00011-022-01664-1.