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

Area of Science:

• Medicinal Chemistry
• Inorganic Chemistry
• Computational Chemistry

Background:

• Antimicrobial resistance (AMR) is a growing global health threat, necessitating the development of novel antimicrobial agents.
• Inorganic and organometallic complexes offer a largely unexplored resource for novel antibiotic discovery.

Purpose of the Study:

• To design and synthesize novel fac-Re(I) tricarbonyl complexes with potential antimicrobial activity.
• To evaluate the antibacterial efficacy of these complexes against Staphylococcus aureus.
• To explore the potential of computer-aided drug design (CADD) and scaffold-hopping for antibiotic discovery.

Main Methods:

• Utilized computer-aided drug design (CADD) with a scaffold-hopping approach to identify promising rhenium(I) complex candidates.
• Synthesized fac-Re(I) tricarbonyl complexes featuring clotrimazole and modified 2,2'-bipyridine ligands.
• Evaluated the antibacterial activity against methicillin-sensitive and methicillin-resistant S. aureus strains, determining minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).
• Performed molecular docking studies against a homology model of the S. aureus MurG enzyme.

Main Results:

• The synthesized rhenium(I) complexes exhibited antibacterial activity comparable to the reference compound.
• Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were similar to the scaffold compound.
• Docking scores supported the binding affinity of the complexes to the S. aureus MurG enzyme.

Conclusions:

• The study demonstrates the successful application of scaffold-hopping CADD for the de novo design of novel antimicrobial agents.
• The developed rhenium(I) complexes represent a potential new class of antibiotics.
• This approach offers a more cost- and time-efficient strategy for discovering new antibiotics to combat AMR.