•23 novel pyrimidine derivatives were designed and synthesized via a ring-opening strategy.•Antiproliferative activity of these compounds was evaluated.•Compound 7w exhibited much stronger antitumor activity than fluorouracil.•Flow-activated cell sorting analysis suggested that compound 7w mainly arrested HepG2 cells in G2/M stage.In order to discover new anticancer drug leads, a series of novel alkylamino pyrimidine derivatives were designed and synthesized based on our previous work via a ring-opening strategy. Biological evaluation with four human cancer cell lines (MDA-MB-231, A549, HepG2, and MCF-7) showed that most of these compounds possessed moderate to potent antiproliferative activities. The most promising compound 7w displayed a three-fold improvement compared with commercial anticancer drug fluorouracil in inhibiting HepG2 cell proliferation with IC50 value of 10.37 μM. Moreover, flow-activated cell sorting analysis suggested that compound 7w mainly arrested HepG2 cells in G2/M stage. Hence, it could serve as a promising lead for the design of novel anticancer small-molecule drugs.A series of novel alkylamino pyrimidine derivatives were designed and synthesized based on our previous work via a ring-opening strategy. Biological evaluation showed that some compounds possessed potent antiproliferative activities.

Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50 values of 0.37, 2.94, and 31.31 μM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.

•26 novel 1,2,4-triazolo [3,4-b][1,3,4] thiadiazines bearing furan and thiophene nucleus were synthesized.•Antiproliferative activity of these compounds was evaluated.•The most promising compound 32 displayed much stronger antitumor activity than fluorouracil.•Compound 32 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in PC-3 cells.Twenty-six novel 1,2,4-triazolo [3,4-b][1,3,4] thiadiazines containing furan and thiophene nucleus were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that most of the compounds showed moderate to potent antiproliferative activities against four cancer cell lines, PC-3, HepG2, A549, and MCF-7. Particularly, compound 32 showed eleven-, three-, and two-fold improvement compared to positive control fluorouracil in inhibiting HepG2, PC-3, and A549 cell proliferation with IC50 values of 5.09, 3.70 and 12.74 μM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 32 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in PC-3 cells. These encouraging results should provide important information for the development of new anticancer agents.Compound 32 exhibited eleven-, three-, and two-fold improvement compared to fluorouracil in inhibiting HepG2, PC-3, and A549 cell proliferation with IC50 values of 5.09, 3.70 and 12.74 μM, respectively.

•24 novel 2,4-diaminopyrimidines were synthesized via a one-pot reaction.•Antiproliferative activity of these compounds was evaluated.•Two compounds displayed much stronger antitumor activity than Fluorouracil.•Compound 28 displayed a significant effect on G2/M cell-cycle arrest in MDA-MB-231.A series of novel 2,4-diaminopyrimidines containing piperidine and piperazine moieties were synthesized via an efficient one-pot methodology. The bioassay tests demonstrated that compounds 27 and 28 displayed much stronger antitumor activities against four human cancer cell lines (HepG2, A549, MDA-MB-231 and MCF-7) than positive control fluorouracil. Particularly, compound 28 showed a two-fold improvement compared to fluorouracil in inhibiting MDA-MB-231 and A549 cell proliferation with IC50 values of 7.46 and 12.78 μM, respectively. Further flow-activated cell sorting analysis revealed that the most promising compound 28 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in MDA-MB-231 cells.

A series of novel isoindoline-1,3-diones containing 1,2,4-triazole moiety were synthesized via a one-pot reaction. Bioassay indicated that compounds 33, 35, 37 and 39 exhibited much higher activities against Botryodiplodia theobromae than commercial fungicide triadimefon at the dosage of 150 mg/L. Most interestingly, compounds 36, 37 and 45 displayed much stronger antitumor activities against four human cell lines than positive control Fluorouracil. Particularly, compound 37 had four-fold improvement compared to Fluorouracil in inhibiting A549 and HepG2 cell proliferation with IC50 values of 6.76 and 9.44 μM, respectively. Further flow-activated cell sorting analysis revealed that compound 37 displayed apoptosis-inducing effect on HepG2 cells in a dose-dependent manner. These encouraging results could be helpful for the development of new antitumor compounds.Graphical abstractA novel series of isoindoline-1,3-diones bearing 1,2,4-triazole moiety have been designed, synthesized and evaluated for in vitro antifungal activity and cytotoxicity.Highlights► 38 Novel isoindoline-1,3-diones were synthesized via a one-pot reaction. ► Antifungal and cytotoxic activities of these compounds were evaluated. ► Antifungal studies of the novel compounds showed promising activity. ► Three compounds displayed much stronger antitumor activity than Fluorouracil.

A series of 3,4-disubstituted-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazoles and some novel 5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles bearing 3,4,5-trimethoxyphenyl moiety were synthesized and screened for their anticancer activity. The preliminary bioassay results indicated that compounds 14 and 16 showed much stronger cytotoxicity than Doxorubicin against HepG2 cell lines with IC50 values of 0.58 and 3.17 μM, respectively. Meanwhile compound 16 also exhibited a broad spectrum of antitumor activity against MCF-7 and MKN45 with IC50 values of 10.92 and 13.79 μM, respectively.