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.

Keywords: Staphylococcus aureus MurG; clotrimazole; docking; rhenium.

Figure 1

Schematic diagram of the membrane steps of the bacterial peptidoglycan synthesis pathway showing the known inhibitory function of 1. For more details about the scheme, see [46].

Figure 2

Schematic diagram of the conventional docking approach used to identify ‘hit’ complexes of Re-ctz derivatives.

Figure 3

Molecular structure of Re-ctz complexes used for molecular docking with receptor SaMurG. Note that the # refers to the complexes. The corresponding 4,5-pinene and 5,6-pinene bipyridine are referred as L# in the text. The * refers to the specific nitrogen atom coordinated to the Re center as depicted for the complex on the top left.

Scheme 1

Top and bottom respectively: general synthetic procedures and chemical structures of 4,5-pinene and 5,6-pinene bipyridine ligands (L#) and of Re complexes. For ligand synthesis, conditions are: (a) stepwise 1. EtOH/AcOH NH₄OAc; 2. NaNO₂, HBr, 0°; 3. CuBr, HBr, 70°; 4. Zn/[Ni(PPh₃)₄Cl₂], DMF [55]. (b) NH₄OAc/AcOH, 100° [47].

Figure 4

Crystal structures of complex 1. Thermal ellipsoids are at 30% probability. Hydrogen atoms are omitted for clarity.

Figure 5

Antibacterial activity of different Re-ctz complexes against (a) S. aureus wild-type strain, and (b) S. aureus methicillin-resistant type strain, respectively.

Figure 6

Full (A) and detail (B) view of the binding region of computer-generated lowest energy pose of complex 4 in SaMurG homology model.

Figure 7

Representation of the structure of the homological model for SaMurG based on the residue hydrophobicity.

Figure 8

Comparison between the PBD: 1NLM and new model. Aligned models using green—predicted structure with ESMFold (implemented in SAMSON); red—Swiss model server and blue—PDB: 1NLM.