Nickel N‐heterocyclic carbene complexes based on xanthines: Synthesis and antifungal activity on Candida sp.

Abstract

Invasive fungal diseases affect more than two million people worldwide. The increasing incidence of invasive fungal infections is the result of many factors, including an increase in the resistance to current drugs. As such, there is an urgent need to obtain new drugs that are efficient, selective, and able to overcome existing resistance mechanisms. Candida yeasts are responsible for more than 70% of all nosocomial invasive fungal diseases. In this work, we describe the synthesis of nickel (II)(NHC) complexes based on xanthines, by direct metalation of xanthinium salts with nickelocene NiCp2to yield [NiCpI(NHC)] complexes. For methyl caffeine, a biscarbene complex [NiCp(NHC)2]+is also formed, resulting from carbene dissociation from the corresponding monocarbene. [NiCpI(NHC)] complexes are active as antifungals for Candida yeasts and show toxicity for human cells (HeLa) that is dependent on the substitution of N7 of the xanthine moiety. The biscarbene complex 5[NiCp(NHC)2]+is highly selective for Candida glabrata and shows very low toxicity for human cells, being a promising candidate for selective treatment of C. glabrata infections.

Pd–PEPPSI N-Heterocyclic Carbene Complexes from Caffeine: Application in Suzuki, Heck, and Sonogashira Reactions

“…The presence of the imidazole ring in xanthines makes them attractive precursors to NHCs with a modified backbone from the classical imidazol-2-ylidenes . NHCs derived from xanthines play important roles in medicinal chemistry as antimicrobial and antiproliferative agents as amply demonstrated by the groups of Youngs and co-workers, Casini and co-workers, Willans and co-workers, and others. , In sharp contrast, very few examples of xanthines as NHC ligands for transition-metal catalysis have been reported. − In particular, the development of Pd complexes of NHC ligands derived from xanthines is only in its infancy and remains unexplored. − Despite the importance of Pd–PEPPSI systems bearing N -heterocycles as ancillary ligands, , which are increasingly more popular as Pd­(II)–NHC complexes in organic synthesis due to rapid access, versatility, and air- and moisture-stability, surprisingly, Pd–PEPPSI complexes derived from xanthines have not been reported.…”

Antitumor Activity and Reductive Stress by Platinum(II) N‐Heterocyclic Carbenes based on Guanosine**

“…The crystal structure confirms the trans orientation for the two phosphines. The N7−C8−N9 angle is 106.7(5)°, identical to other metal NHCs based on caffeine [17–19] . The Pt−C8 bond length is 2.064(5) Å, longer than in the related systems having chlorine and bromine as co‐ligands, [20,21] probably due to the trans influence of the hydride [15] …”

“…The N7À C8À N9 angle is 106.7(5)°, identical to other metal NHCs based on caffeine. [17][18][19] The PtÀ C8 bond length is 2.064(5) Å, longer than in the related Scheme 1. Methylation of complex 1 with methyl triflate, affording the NHC 4.…”

Recent advances in catalytic and electrocatalytic applications of half‐sandwich nickel(0/II) N–heterocyclic carbene complexes

“…6 Nickelocene-derived complexes [with cyclopentadiene (Cp) or substituted cyclopentadiene (Cp R )] ligands have been extensively studied for their applications in both catalysis and bioorganometallic chemistry. 7 The molecular orbital (MO) diagram of the M-Cp bond illustrates that the wave functions, ψ 4 and ψ 5 , are highly energetic as compared to the 3d orbital of the metal, and thus, the orbitals of the Cp module do not effectively overlap with the orbitals of the metal atom. This makes Cp a poor π acceptor ligand and facilitates the non-Cp ligand such as N-heterocyclic carbene (NHC), a good π acceptor.…”

“…On the contrary, the advancements in the field of metallocene‐based catalysts possessing first‐row transition metals sparked extensive growth in the fields of both, organometallic chemistry and homogeneous catalysis from the time of the discovery of ferrocene 6 . Nickelocene‐derived complexes [with cyclopentadiene (Cp) or substituted cyclopentadiene (Cp R )] ligands have been extensively studied for their applications in both catalysis and bioorganometallic chemistry 7 . The molecular orbital (MO) diagram of the M–Cp bond illustrates that the wave functions, ψ 4 and ψ 5 , are highly energetic as compared to the 3d orbital of the metal, and thus, the orbitals of the Cp module do not effectively overlap with the orbitals of the metal atom.…”