In Vitro Antimalarial Activity of a Series of Cationic 2,2‘-Bipyridyl- and 1,10-Phenanthrolineplatinum(II) Benzoylthiourea Complexes

Abstract

We have synthesized a series of novel 2,2'-bipyridyl and 1,10-phenanthroline benzoylthiourea complexes of platinum(II) with various substituents on the bipyridyl and phenanthroline ligands. All of these square-planar mixed-ligand cationic complexes were found to form moderately strong complexes with ferriprotoporphyrin IX in 40% aqueous DMSO (log K ranging from 4.81 to 6.24). The complexes also all inhibit beta-hematin (synthetic hemozoin or malaria pigment) formation in acetate solution. Four of the compounds were found to exhibit in vitro antimalarial activity, with (N-benzoyl-N',N'-di(2-hydroxyethyl)thioureato)(4,4'-di-tert-butyl-2,2'-bipyridyl)platinum(II) chloride being particularly active. These active complexes exhibited equally strong activity against both the D10 chloroquine sensitive and K1 chloroquine resistant strains of malaria parasite. Cytotoxicity testing of the four most active compounds shows that they exhibit selective activity against malaria parasites with selectivity indices greater than 85. These compounds represent a new family of potential antimalarials.

N-(Dibenzylcarbamothioyl)-3-methylbutanamide: Crystal structure, Hirshfeld surfaces and antimicrobial activity

“…For example, acylthiourea derivatives and their Co(III) complexes have shown antibacterial [13] and antifungal [14] activities. Ni(II) complexes, containing benzoylthiourea ligands, have shown cytotoxicity against T47D cell [15] and according to the investigations water soluble platinum(II) benzoylthiourea complexes have shown considerable antimalarial activity [23,24]. Very recently, there have been many studies on noncovalent interactions acting on the crystal structure and packing of sulfur-containing compounds [25].…”

Cation–π induced aggregation of water-soluble [PtII(diimine)(Ln-S,O)]+complexes studied by1H DOSY NMR and TEM: from ‘dimer aggregates’ in acetonitrile to nano-aggregates (‘metallogels’) in water

“…[1][2][3][4][5] Our interest in the chemistry of planar, cationic mixed-ligand Pt II complexes of the general type [Pt II (diimine)(L n -S,O)] + (where diimine is 2,2-bipyridine or 1,10-phenanthroline and HL n -S,O are various chelating N-acyl-N,Ndialkylthioureas) arises from their interesting biological activity ranging from potential anti-malarial activity 6 to DNAintercalation and demonstrable in vivo activity toward bacterial E. coli AB1886 (uvr A) cultures. 7 Preliminary work also shows that such complexes undergo some interesting DNA-templated 'biomineralization'.…”

“…7 Preliminary work also shows that such complexes undergo some interesting DNA-templated 'biomineralization'. 8 The in vitro anti-malarial activity 6 (1,10-phenanthroline Table 1. Doty and Myers attributed similar trends in ΔΔ r S 0 for dimerization of protein moieties to the dehydration of charged groups upon aggregation, while Kauzmann and Scheraga suggested that this trend may be due to non-covalent hydrophobic bonding of non-polar groups increasing the degree of freedom of the water molecules close to hydrophobic groups.…”

Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)− ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities

“…As our interests lie also in the area of antiparasitic drugs [42,43] and since a few Pt(II) [44] and Pd(II) based complexes [45] with antimalarial activity (in the micromolar range) have been reported, we also tested the potential of the free ligands (1a-1c) and the complexes 2a-5c against the chloroquine-susceptible strain (3D7) and the chloroquine-resistant strain (W2) of Plasmodium falciparum.…”