ABSTRACT
Diflumetorim is a member of pyrimidinamine fungicides that possess excellent antifungal activities. Nevertheless, as reported that the activity of diflumetorim to corn rust (Puccinia sorghi) was not ideal (EC50â¯=â¯53.26â¯mg/L). Herein, a series of novel pyrimidinamine derivatives containing phenyl-thiazole/oxazole moiety were designed based on our previous study and the structural characteristics of diflumetorim, synthesized and bioassayed to discover novel fungicides with excellent antifungal activities. Among these compounds, T18 gave the optimal fungicidal activity, which respectively offers control effects with EC50 values of 0.93â¯mg/L against P. sorghi and 1.24â¯mg/L against E. graminis, significantly superior to commercial fungicides diflumetorim, tebuconazole, and flusilazole. Cell cytotoxicity results suggested that compound T18 has lower toxicities than diflumetorim. Furthermore, DFT calculation indicated that the phenyl-thiazole/oxazole moiety plays an unarguable role in the improvement of activity, which will contribute to designing and developing more potent compounds in the future.
Subject(s)
Antifungal Agents/pharmacology , Drug Design , Fungicides, Industrial/pharmacology , Oxazoles/pharmacology , Pyrimidines/pharmacology , Thiazoles/pharmacology , Alternaria/drug effects , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Ascomycota/drug effects , Botrytis/drug effects , Density Functional Theory , Dose-Response Relationship, Drug , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Gibberella/drug effects , Microbial Sensitivity Tests , Molecular Structure , Oxazoles/chemistry , Phytophthora/drug effects , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
The relationship between chemical structure and in vitro cytotoxic activities of a series of azastibocine-framework organoantimony(III) halide complexes against cancerous (HepG2, MDA-MB-231, MCF-7 and HeLa) and nonmalignant (HEK-293) cell lines was studied for the first time. A positive correlation between cytotoxic activity and the length of NâSb coordinate bond on azastibocine framework of same nitrogen substituent was observed. By comparison, the organoantimony(III) complex 6-cyclohexyl-12-fluoro-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine (C4) exhibited the highest selectivity index, giving a IC50(nonmalignant)/IC50(cancerous) ratio of up to 8.33. The results of cell cycle analysis indicated that the inhibitory effect of C4 on the cellular viability was caused by cell cycle arrest mainly at the S phase. The necrosis induced by C4 was confirmed by the Trypan blue dye exclusion test and the increase of lactic dehydrogenase (LDH) released in the culture medium. Furthermore, evaluation of the levels of intracellular reactive oxygen species (ROS) in MDA-MB-231â¯cells, by quantifying the relative fluorescence units (RFU) using spectrofluorometer, indicated that cytotoxic activity of C4 is dependent on the production of ROS. This work established the correlation between cytotoxic activity and NâSb inter-coordination, a finding that provided theoretical and experimental basis for in-depth design of antimony-based organometallic complexes as potential anticancer agents.