Computer-Aided Drug Design and Synthesis of Rhenium Clotrimazole Antimicrobial Agents

Abstract

In the context of the global health issue caused by the growing occurrence of antimicrobial resistance (AMR), the need for novel antimicrobial agents is becoming alarming. Inorganic and organometallic complexes represent a relatively untapped source of antibiotics. Here, we report a computer-aided drug design (CADD) based on a ‘scaffold-hopping’ approach for the synthesis and antibacterial evaluation of fac-Re(I) tricarbonyl complexes bearing clotrimazole (ctz) as a monodentate ligand. The prepared molecules were selected following a pre-screening in silico analysis according to modification of the 2,2′-bipyridine (bpy) ligand in the coordination sphere of the complexes. CADD pointed to chiral 4,5-pinene and 5,6-pinene bipyridine derivatives as the most promising candidates. The corresponding complexes were synthesized, tested toward methicillin-sensitive and -resistant S. aureus strains, and the obtained results evaluated with regard to their binding affinity with a homology model of the S. aureus MurG enzyme. Overall, the title species revealed very similar minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values as those of the reference compound used as the scaffold in our approach. The obtained docking scores advocate the viability of ‘scaffold-hopping’ for de novo design, a potential strategy for more cost- and time-efficient discovery of new antibiotics.

Silver(i) complexes containing antifungal azoles: significant improvement of the anti-Candida potential of the azole drug after its coordination to the silver(i) ion

“…Besides that, very recently, the crystal structure of fac -tricarbonylrhenium( i ) complex bearing two different ligands, monodentate clotrimazole and bidentate 2,2′-bipyridine, has been reported. 26 Complexes 1 and 3 show relatively simple structures, both containing two monodentately N3-coordinated azole ligands (econazole and clotrimazole, respectively) forming a complex cation with linear geometry as expected (Fig. 1).…”

“…S3–S5†) and their assignment was performed based on the NMR data reported in the literature for the studied azoles, whose 1 H NMR spectra were recorded in different solvents. 24,26,35 As can be seen in Fig. S3–S5,† most of the 1 H resonances for the coordinated azoles are downfield shifted concerning those for the uncoordinated ligand.…”

Discovery of antibacterial manganese(i) tricarbonyl complexes through combinatorial chemistry

“…The antifungal clotrimazole (Clo) has been utilised as a ligand in several other studies and found to convey some level of biological activity that goes beyond the activity of the parent compound. 17,22,45 We have hence included it in our studies as a means to compare our compounds to others reported in the literature.…”

Progress and future of the computational design of antimicrobial peptides (AMPs): bio-inspired functional molecules

“…However, their targets and mechanism of action need further research. [3][4][5] Microbial metabolites are the source of many existing antibiotics and other medicines. For their high diversity and broad bioactivity spectra, short peptides are among the most widely studied secondary metabolites, and the large group of antimicrobial peptides (AMPs) produced by bacteria has been used to treat bacterial, fungal, and viral infections and even cancer.…”