A new series of bioactive Mo(V)2O2S2-based thiosemicarbazone complexes: Solution and DFT studies, and antifungal and antioxidant activities

Molybdenum (Mo) is present as trace element everywhere in nature, both in soils and in living organisms. Present in >50 enzymes, this element plays a crucial role in many biological processes, such as nitrogen assimilation by plants [[1], [2], [3]]. This implication in biology have prompted many authors to develop biomimetic Mo-based coordination complexes. In particular, many coordination complexes based on clusters [Mo(V)2O2E2]2+ (where E is an μ-oxo or a μ-sulfido bridging group) have been developed as biomimetic models for enzymes since the 1960s [[4], [5], [6]]. In these clusters, the two Mo(+V) are bound through a Mosingle bondMo bond, which renders these complexes diamagnetic and perfectly stable in air and in usual solvents but, surprisingly, the biological properties of such complexes have only recently been studied [[7], [8], [9], [10], [11]].

On the other hand, thiosemicarbazone ligands constitute a fascinating class of polydentate organic ligands of general formula R1R2C=N-NH-CS-NR3R4 (see Scheme 1) for which chemists can easily play on the nature of substituents R1, R2, R3 and R4.

This offers a huge panel of ligands capable of giving thousands of coordination complexes with transition metals [[12], [13], [14], [15]], which have received considerable attention in many fields, such as biology and medicine [[16], [17], [18], [19], [20], [21], [22], [23], [24], [25]]. Interestingly, despite the very large number of transition metal thiosemicarbazone complexes reported in the literature, molybdenum complexes are much rarer and often reported with Mo(VI)-dioxo moieties such as MoO2(L)–type complexes (where L is a tridentate thiosemicarbazone ligand), exhibiting antioxidant [26], antitumoral [27] and antibacterial [28] properties. Mo(+V) complexes are very scarce [[29], [30], [31], [32]], which recently prompted us to develop a new family of [Mo(V)2O2S2]2+-based thiosemicarbazones complexes with a wide panel of thiosemicarbazone ligands bearing various R1, R2, R3 and R4 substituents [33]. 14 new complexes based on [Mo(V)2O2S2]2+ have thus been synthesized, revealing unusual coordination modes of thiosemicarbazone ligands. Indeed, in 3d transition metal thiosemicarbazone complexes, 5-membered chelate rings are usually observed around the metal and the ligand are usually tridentate of types O,N,S or N,N,S. In the case of the coordination of [Mo(V)2O2S2]2+ the monoprotonated ligands act as bidentate N,S ligands with the cluster [Mo(V)2O2S2]2+ and 4-membered chelate rings are evidenced around Mo atoms by X-ray diffraction and by NMR studies in solutions, for giving essentially neutral complexes of stoichiometry cluster:ligand = 1:2. Some examples of structures obtained in our previous work are depicted in Fig. 1.

Surprisingly, studies of this new class of [Mo(V)2O2S2]2+-thiosemicarbazone complexes showed that the imino group and the R1 group never participate in the coordination with Mo, which contrasts with classical 3d transition metal complexes. Furthermore, we have shown that the nature of R2 also plays an important role. Indeed, when R2 = H, the formation of two isomers in solution in cis and trans configurations is systematically observed (see Fig. 1), while we identified up to 8 isomers in solution when R2 = Me, due to a probable competition between the coordination of the imino group vs the coordination of the azomethinic N atom and thus between a 4- or 5-membered chelate ring on each Mo atom.

Very recently, the biological properties for these 14 new complexes were screened by Fuior et al. [34] It was evidenced that the Mo2O2S2-based thiosemicarbazone complexes are of interest for biology and that the activity strongly depends on the nature of the R1 group. When R1 is a pyridine ring, a good activity of the complexes as antifungal is measured, while when R1 is a phenol the antitumoral properties are enhanced. It is worth noting that for antifungal activity a good activity against Cryptococcus neoformans is measured for all complexes, while the activity against Candida albicans appears good only for complexes bearing pyridine derivatives. Finally, all complexes exhibit antioxidant properties better than TROLOX but the origin of the process was not established. Besides, the formation of mixtures of isomers constitutes a severe drawback for the interpretation of results in biology and ligands alone were only partially measured. The present study aims to address the issues evidenced by Fuior et al. with this new class of Mo2O2S2-based thiosemicarbazone complexes [33,34]:

Controlling the formation of mixtures of isomers by introducing steric constraints.

Changing the nature of R1 group by a non-coordinative group to evaluate the impact on antifungal activity.

Understanding the origin of the antioxidative properties, ligand, or molybdic cluster.

To address these issues, we synthesized 5 new ligands and the corresponding [Mo(V)2O2S2]2+ complexes. To limit the formation of isomers, the substituents R4 = Me or H, R3 = H, and R2 = H were fixed, whereas we varied the nature of aldehyde in R1. Intuitively, if we want to favour the formation of a single isomer, we can for example introduce steric constraints between ligands. Besides, since R1 has been shown to be not involved in coordination with Mo centres, we don't necessarily need a coordinating group present in R1. Consequently, we introduced in R1 position a dimethylbenzene group for ligands HL1 and HL2, 3- or 5-methoxy-salicyladehyde for H2L3 and H2L4, and the bulky substituent diphenylamine-benzaldehyde for ligand HL5 (see Scheme 2). Each of them thus displays bulkier R1 group than those used in our previous works in the hope of preventing isomers formation upon complexation with [Mo(V)2O2S2]2+. Furthermore, the ligands HL1 and HL2 possess a non-coordinative group as R1, which will permit to complete our previous studies, notably against fungi.

In this paper, a special attention is paid to combining NMR experimental and DFT studies to assess the effect of the variation of R1 on the number of species formed in solution, so to better understand the preferential formation of cis or trans isomers. The biological activity as antifungal and antioxidant is evaluated both for ligands and complexes, notably to evidence some selective properties. DFT calculations were performed on the ligands and cis and trans isomers of the complexes with the aim to determine the electronic levels and the nature of the frontier orbitals in the ligands and the complexes and to better understand the antioxidant activities of the complexes.

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