Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance

Abstract

Fourteen novel arene Ru , and cyclopentadienyl (Cp ) Rh and Ir complexes containing an N,N'-chelated pyridylimino- or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X-ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC values of 0.10-2.0 μm in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis. They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC <6.3 μm), while sulfadoxine showed no antitubercular activity. An increase in the size of both the Cp ligand and the aromatic imino substituent increased hydrophobicity, which resulted in an increase in antiplasmodial activity.

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

“…Most notably, complexation with the IrCp* moiety has been shown to restore the potency of antimalarial drugs that have experienced total clinical resistance. Chellan and colleagues demonstrated this upon their exploration of NˆN-chelated iridium analogues of the clinical antimalarial drug, sulfadoxine (21), which is facing full resistance by P. falciparum strains ( Figure 5) [30]. This group synthesized a series of N,N -chelate pyridylimino- (22) or quinolylimino-(23) IrCp* complexes, functionalized with sulfadoxine ( Figure 5), and evaluated their antiplasmodial activity against P. falciparum strains.…”

“…Interrogation of complexation effects and influence of substitution effects on the benzene ring revealed similar SAR trends as the iridium derivatives (7-10) previously discussed. Likewise, Chellan et al also studied the antiplasmodial potency of the rhodium(III) counterparts (63-64) of the organometallic iridium(III) pyridyl-and isoquinolyl-sulfadoxine conjugates (22-23, Figure 5) against CQS 3D7 and NF54 strains, as well as resistant Dd2 parasites, which generally displayed a significant improvement in activity relative to the Ir(III) complexes across all strains ( Figure 15) [30]. Again, the generated SAR trends were similar for both types of complexes, as discussed earlier.…”

“…Chemical structures of IrCp* complexes based on the sulfadoxine scaffold and their corresponding IC 50 values[30].…”

Metal–Peptide Complexes as Promising Antibiotics to Fight Emerging Drug Resistance: New Perspectives in Tuberculosis

“…Several ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate) already demonstrated potential anti-Tb activity [109,110]; more recently, novel arene Ru, cyclopentadienyl (Cpx) Rh and Ir complexes containing an N,N'-chelated pyridylimino or quinolylimino ligand functionalized with the sulfadoxine were tested: in these complexes, the imino and pyridyl/quinolyl nitrogens provided an N,N-chelation site for the metal and exhibited potent antiplasmodial activity with IC 50 values in the low micromolar range. An increase in the size of both the Cpx ligand and the aromatic imino substituent increased hydrophobicity and antiplasmodial activity [111].…”

Iridium piano stool complexes with activity againstS. aureusand MRSA: it is past time to truly think outside of the box

“…Interest in metal based antimicrobial agents is growing, though many of the recent reports feature complexes of metals with organic molecules that are already known to have antimicrobial properties. [20][21][22] Indeed, a new edition of "Metals in Medicine" has a larger section on antimicrobials than did the previous edition, but there still, the bulk of the section deals with complexes of known drugs. 23 Lately, we have reported on a class of what are known as "halfsandwich" metal complexes that can be tuned for activity against mycobacteria 24,25 as well as against S. aureus including MRSA.…”