In vitro toxicity of several dithiocarbamates and structure–activity relationships

Abstract

Dithiocarbamates (DTCs) are chemicals featuring a great chelating capacity. The toxicological study of DTCs is very important in view of their relatively simple synthesis and wide array of sanitary and industrial applications. In this study, the toxicity of some of the more recently synthesized DTCs is determined using an extremely simple bioassay, described in previous studies, based on the inhibition of growth of Escherichia coli (IGEC). The lowest-observed-effect concentration (LOEC), the median effective concentration (EC(50)) and no-observed-effect concentration (NOEC) of the following sodium dithiocarbamates was determined: N-benzyl-N-methyldithiocarbamate x 2H(2)O, N-benzyl-N-isopropyldithiocarbamate x 3H(2)O, N-benzyl-N-ethyldithiocarbamate x 2H(2)O, N-butyl-N-methyldithiocarbamate x 2H(2)O, N,N-dibenzyldithiocarbamate x 2H(2)O and N-benzyl-2-phenethyldithiocarbamate x 4H(2)O. Our results showed N,N-dibenzyl-DTC to be the least toxic of the tested substances, with an EC(50) value of 1,269.9 micro g ml(-1), whereas N-butyl-N-methyl-DTC and N-benzyl-N-methyl-DTC, with respective EC(50) values of 14.9 micro g ml(-1) and 23.5 micro g ml(-1), were the most toxic. Regression analysis showed, through exponential models, that the degree of toxicity of this group of substances correlated with the molecular weight of the compound, the molecular weight of the smallest chemical radical linked to the dithiocarbamate group and the number of benzene rings present in the molecule. The consideration of these models allows us to establish that in general terms the toxicity of DTCs decreases exponentially with a greater molecular weight and the number of benzene rings.

More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

“…Furthermore, we suggest that our proposed 24a derivatives, 24a-6 (MW = 251.27 Da), 24a-17(MW = 277.31 Da), 24a-18(MW = 275.29 Da), 24a-19 (MW = 299.32 Da) and 24a-21 (MW = 303.35 Da) vs 24a (MW = 163.25 Da ) might have a lower toxicity, in agreement with experimental data indicating that these effects decrease with increased molecular weight 6 . Focusing on the toxicity of these derivatives, based on experimental results showing that a higher number of benzene rings leads to reduced toxic effect 6 we may suggest that the higher count of hydrophobic atoms will also induce a low toxic effect.…”

“…Besides, in agreement with experimental data 1,2,6 showing that descriptors like compounds structure and size are important not only for inhibitory effects of DTC but also for their side effects, our 2D-QSAR models are able to predict both the inhibitory activity of DTCs 1 and their side effects. Our major goal is to better understand the inhibitory mechanism and to propose new effective DTCs derivatives to be used in anti-cancer and antiglaucoma therapies.…”

“…Despite the positive pharmacological applications of DTCs, toxic and teratogenic effects of these compounds were reported [6][7][8][9] . These effects are induced by great chelating capacity of DTCs, especially in fish species 7,8 .…”

“…These effects are induced by great chelating capacity of DTCs, especially in fish species 7,8 . Segovia et al 6 demonstrate in their SAR study that the degree of toxicity of DTCs correlates with three molecular features: (i) molecular weight of the compound; (ii) the molecular weight of the smallest chemical radical linked to the DTC group; and (iii) the number of benzene rings in the molecule. Their results show that, in general terms, the toxicity of DTCs decreases exponentially with increasing molecular weight and the number of benzene rings.…”

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

“…20 Nevertheless, the overall nephroprotective benefits of DEDTNa are somewhat limited by the acute toxicity profile of free (i.e., not coordinated) dithiocarbamates. 22 On the basis of these considerations, we have been designing a number of gold(III)-dithiocarbamato complexes potentially able to combine the well-known antitumor properties of the metal center with the promising chemoprotective function of dithiocarbamates. The rationale of our strategy is based on the chemical properties of the dithiocarbamato moiety (ANCSS À ).…”