Title:Synthesis, Molecular Docking Studies and Antibacterial Activities of Novel Monocationic Indole-benzimidazole Derivatives
Volume: 17
Issue: 7
Author(s): Zeynep Ates-Alagoz*, Mehmet Murat Kisla, Hakan Goker and Sulhiye Yildiz
Affiliation:
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara,Turkey
Keywords:
Synthesis, indoles, benzimidazolecarboxamides, antibacterial activities, molecular docking, pyruvate kinase.
Abstract:
Background: Finding efficient therapy against hospital-acquired MRSA infections has
become rather important in the last decade. To this end, inhibition of the enzyme pyruvate kinase
(PK) is being investigated for antibacterial activity, since this enzyme controls energy generation
and metabolic flux distribution. Our main scaffold consists of benzimidazole and indole rings
fused together. Both rings are famous for antibacterial properties and promising anti-MRSA compounds
including indole ring.
Methods: Several 1-substituted-2-(1H-indol-3-yl)-N-substituted-1H-benzimidazole-5-carboxamidine
analogues were developed, synthesized and their antibacterial activities were evaluated
against Staphylococcus aureus (ATCC 25923), Methicillin resistant Staphylococcus aureus
(MRSA) (ATCC 43300), and Staphylococcus epidermidis (ATCC 12228) by using tube dilution
method. Molecular docking analysis with a characteristic protein called MRSA- Pyruvate Kinase
has been conducted for the assessment of the activities of our compounds against Methicillinresistant
S. aureus (MRSA).
Results: Among all the tested compounds, the most potent compound 36 had MIC values as 3.12,
3.12 and 6.25 μg/mL against S. aureus, Methicillin-resistant S. aureus (MRSA), and S. epidermidis,
respectively. This compound had much better docking energy value than standard ampicillin
and also created the link between two residues in different monomers of PK.
Discussion: This approach of using indol-amidine conjugate systems as anti-MRSA agents may
include MRSA-PK as potential target. To further increase the affinity, some other H-bonding parts
may be added. By doing so, another bridge with Ile361 residues on both sides can be created. Our
compounds tend to violate log P limit of Lipinski, therefore some optimizations with formulation
can be made.
Conclusion: This study mainly includes the design, synthesis and optimization of indolebenzimidazole-
amidine derivatives. Docking studies confirmed our results, since our most potent
hit compound 36 created the necessary interactions between two chains of MRSA-PK. Further optimization
can be considered to increase drug ability.