Thiocarbamoyl Disulfides as Inhibitors of Urease and Ammonia Monooxygenase: Crystal Engineering for Novel Materials

The environmental sustainability of soil nitrogen fertilization is essential for the primary production of food for an expanding human population. In this framework, the control of soil enzymatic activities that impact the release of N-based compounds either in the atmosphere or in the underground waters is critical. The two enzymes that act as key players in the biogeochemical cycle of nitrogen are urease and ammonia monooxygenase (AMO), respectively, nickel- and copper-dependent enzymes. This article reveals the high efficacy of three molecules of the thiurams family, namely, thiram (tetramethylthiuram disulfide, TMTD), disulfiram (tetraethylthiuram disulfide, TETD), and tetraisopropylthiuram disulfide (TIPTD) as inhibitors of both the activities of jack bean (Canavalia ensiformis) urease (JBU) and Nitrosomonas europaea AMO. The water solubility of these compounds was significantly improved by the preparation of three novel inclusion complexes of beta-cydodextrin with TMTD, TETD, and TIPTD by mechanochemical synthesis, using green technology. The resulting beta-CD.thiuram complexes beta-CD.TMTD, (beta-CD)(2)-TETD, and (beta-CD)(2).TIPTD were all characterized by powder X-ray diffraction, thermogravimetric analysis, and solid-state NMR. A conformational polymorph of TIPTD was also detected and isolated via hot stage microscopy, and structurally characterized by single-crystal X-ray diffraction. Biological tests of enzymatic inhibition performed on JBU and AMO with the beta-CD.thiuram complexes showed the same inhibition efficacy as the isolated molecules, suggesting that the active species is, in all cases, the free thiuram, likely in equilibrium with the adduct in solution. These results have a great potential for improving the nitrogen use efficiency of soil fertilizers for a greener environment.