A pyrazine amide – 4-aminoquinoline hybrid and its rhodium and iridium pentamethylcyclopentadienyl complexes; evaluation of anti-mycobacterial and anti-plasmodial activities

Abstract

The synthesis and characterization of N-(2-((7-chloroquinolin-4-yl)amino)ethyl)pyrazine-2-carboxamide (<strong>L</strong>), an aminoquinoline – pyrazinamide hybrid, and the complexes (N-(2-((7-chloroquinolin-4-yl)amino)ethyl)pyrazine-2-carboxamide)(cyclopentadienyl) chlorido-rhodium or iridium hexafluorophosphate ([M(<strong>L</strong>)(Cp*)Cl] PF<sub>6</sub>; M = Rh, Ir) and the corresponding chlorido salts ([M(<strong>L</strong>)(Cp*) Cl]Cl; M = Rh, Ir) are described. The ligand and the hexafluorophosphate salts of the metal complexes have been evaluated for anti-plasmodial and anti-mycobacterial activity. The rhodium and the iridium complexes were significantly more active against <em>M. tuberculosis</em> than the free ligand. The crystallographically determined molecular structures of complexes (N-(2-((7-chloroquinolin-4-yl)amino)ethyl)pyrazine-2-carboxamide)(cyclopentadienyl)chlororhodium hexafluoro-phosphate and (N-(2-((7-chloroquinolin-4-yl)amino)ethyl)pyrazine-2-carboxamide)(cyclopentadienyl)chloro-iridium chloride are presented.

Recent Advances in the Biological Investigation of Organometallic Platinum-Group Metal (Ir, Ru, Rh, Os, Pd, Pt) Complexes as Antimalarial Agents

“…Mechanistic studies further suggested that the complexes acted via the inhibition of hemozoin synthesis, which is a pathway unique to the malaria parasite and a crucial detoxification mechanism. [24,25].…”

“…Recently, the research group of Smith reported a series of neutral, cyclometallated Ir(III)Cp* complexes (25), based on the 2-phenylbenzimidazole scaffold (24), showing in vitro antiplasmodial activity against NF54 and K1 strains of P. falciparum ( Figure 6) [31]. The synthesized complexes displayed activities in the low micromolar range against the tested strains.…”

“…It should also be noted that the salicylaldimine ligand was more favorable for plasmodial potency, relative to the picolamine and imidazole ligands. A subsequent study, reported in the following year by the same research group, revealed that coordination with a pyrazine amide ligand ( 10 ) was detrimental for antiplasmodial activity, as the resulting complex was inactive at the highest tested concentration against the NF54 parasite strain ( Figure 2 ) [ 25 ].…”

“…In addition to the bidentate chloroquine-derived N^N - and N^O -chelated Ir(III)ClCp* complexes 7 – 10 ( Figure 2 ), Nordlander and colleagues reported the antiplasmodial activity of Rh(III)ClCp* congeners 59 – 62 exhibiting activity against CQS NF54 and CQR Dd2 P. falciparum strain ( Figure 15 ) [ 24 , 25 ]. These rhodium complexes were more active than their Ir(III)ClCp* variants 7 – 10 in the sub-micromolar range (IC 50 : 0.16–0.209 μM) against the sensitive strain, although less active against the resistant strain (0.20–0.40 μM).…”

“… Chemical structures of N^N - and N^O -coordinated IrCp* complexes and their corresponding IC 50 values [ 24 , 25 ]. …”