Antileishmanial and Anti‐Chikungunya Activity of Cu(I)‐N‐Heterocyclic Carbenes

Abstract

Neglected tropical diseases such as Leishmaniasis and Chikungunya fever are worldwide public health challenges mainly affecting tropical and subtropical countries. One cationic [Cu-(I)(NHC) 2 ] + (4) and two neutral [Cu(I)(NHC)Cl] complexes, where NHC = 1,3-bis(mesityl)imidazole-2-ylidene (IMes) (5) or 1,3-bis-(2,6-diisopropylphenyl)imidazole-2-ylidene (IPr) (6), had their in vitro activity evaluated towards Leishmania amazonensis and Chikungunya virus (CHIKV). The compound (6) inhibited 95 % of L. amazonensis infection in RAW macrophages at 10 μM and 90 % of the CHIKV replication at 2 μM in BHK-21 cells. Otherwise, the other compounds showed higher cytotoxicity in BHK-21 and RAW or lower antiparasitic or antiviral activities.The best activity of compound 6 can be explained by slower ligand exchange with solvent molecules measured by 1 H NMR technique and the best hydrophilic/lipophilic balance (log P = À 0.684 � 0.055) in the series determined by shake flask method. Antioxidant activity measured by reduction of DPPH revealed a moderate redox ability of all complexes. The binding constant of ( 6) with bovine serum albumin (BSA) represents the weakest in the series (10 3 ). The chemical and in vitro evaluation reported here represent a novel application and chemical insights for the design of [Cu(I)(NHC)L] metallodrugs for these infectious diseases.

Synthesis of esters and amides of 2-aryl-1-hydroxy-4-methyl-1H-imidazole-5-carboxylic acids and study of their antiviral activity against orthopoxviruses

“…Imidazole-containing molecules demonstrate a wide variety of antiviral activities. Only recently papers on antiviral activity of imidazole derivatives against Hepatitis C virus 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , Hepatitis B virus [38] , influenza A virus 39 , 40 , dengue virus 41 , 42 , Chikungunya virus [43] , rhabdoviridae 44 , 45 , 46 , 47 , 48 , herpesviridae [49] , Human Cytomegalovirus [50] , HIV-1 [51] and coronaviruses [52] have been published.…”

Unraveling ligand exchange reactions in linear neutral Au(i) and Cu(i) N-heterocyclic carbene complexes for biological applications

“…7,8 Conversely, copper complexes have shown potential as drugs for several diseases, but mostly, the research is limited to academia. 9 The growing interest in copper-based drugs is driven by the fact that copper is an essential element for humans, and cells have the machinery to regulate its absorption and excretion, thereby improving pharmacodynamics. [10][11][12] Cu(I), Ag(I) and Au(I) compounds (family 11) typically have a coordination number of two in a linear arrangement; however, higher coordination numbers and different geometries, such as trigonal and tetrahedral, have been reported.…”

“…Cationic [M(NHC) 2 ] + and neutral [M(NHC)Cl] complexes have been explored as drug chemotypes for anticancer, antibacterial, antiparasitic, and antiviral agents. 5,9,[19][20][21] More recently, derivatives of [M(NHC)Cl] are explored, identifying [Au(NHC)(SCOR)] (where SCOR À = thiocarboxylate ligand) with promising anticancer activity. 22 Modern synthetic approaches for [M(NHC)X] have been developed allowing a wide diversity of applications for these versatile complexes.…”

Gold(I)‐N‐Heterocyclic Carbene Synthons in Organometallic Synthesis

“…[3] For this reason, N-heterocyclic carbenes are also widely used with other transition metals with the aim of developing efficient (photo)catalysts [4] and materials [5] (e. g., OLEDs) as well as new generations of anticancer, [6] antimicrobial [7] and antiviral drugs. [8] Although numerous reviews have summarized the use of gold-NHC complexes in these applications, much less attention has been devoted to the use of gold-NHC complexes as valuable precursors in organometallic syntheses. Many research groups have synthesized gold-NHC complexes which have proven to be particularly reactive towards specific organic and organometallic compounds, providing simple and straightforward synthetic entryways to unprecedented classes of gold complexes with promising biological, catalytic and/or photoemissive properties.…”

“…N ‐heterocyclic carbenes are some of the most explored ancillary ligands in gold chemistry, since the strength of the gold‐NHC bond ensures high stability both in the solid state and in solution, even under physiological conditions [3] . For this reason, N ‐heterocyclic carbenes are also widely used with other transition metals with the aim of developing efficient (photo)catalysts [4] and materials [5] (e. g., OLEDs) as well as new generations of anticancer, [6] antimicrobial [7] and antiviral drugs [8] . Although numerous reviews have summarized the use of gold‐NHC complexes in these applications, much less attention has been devoted to the use of gold‐NHC complexes as valuable precursors in organometallic syntheses.…”