Benzoquinoline Derivatives: A Straightforward and Efficient Route to Antibacterial and Antifungal Agents

Abstract

We report here the design, synthesis, experimental and in silico evaluation of the antibacterial and antifungal activity of some new benzo[f]quinoline derivatives. Two classes of benzo[f]quinolinium derivatives-(benzo[f]quinolinium salts (BQS) and pyrrolobenzo[f]quinolinium cycloadducts (PBQC)-were designed and obtained in two steps via a direct and facile procedure: quaternization followed by a cycloaddition reaction. The synthesized compounds were characterized by elemental and spectral analysis (FT-IR, ¹H-NMR, ¹³C-NMR). The antimicrobial assay reveals that the BQS salts have an excellent quasi-nonselective antifungal activity against the fungus Candida albicans (some of them higher that the control drug nystatin) and very good antibacterial activity against the Gram positive bacterium Staphylococcus aureus. The PBQC compounds are inactive. Analysis of the biological data reveals interesting SAR correlations in the benzo[f]quinolinium series of compounds. The in silico studies furnished important data concerning the pharmacodynamics, pharmacokinetics and ADMET parameters of the BQS salts. Studies of the interaction of each BQS salt 3a-o with ATP synthase in the formed complex, reveal that salts 3j, 3i, and 3n have the best fit in a complex with ATP synthase. Study of the interaction of each BQS salt 3a-o with TOPO II in the formed complex reveals that salts 3j and 3n have the best-fit in complex with TOPO II. The in silico ADMET studies reveal that the BQS salts have excellent drug-like properties, including a low toxicity profile. Overall, the experimental and in silico studies indicate that compounds 3e and 3f (from the aliphatic series), respectively, and 3i, 3j and 3n (from the aromatic series), are promising leading drug candidates.

Keywords: ADMET; SAR/QSAR; antibacterial; antifungal; benzo[f]quinoline; cycloadducts; mechanism of action; molecular docking; salts.

Scheme 1

Design in the class of benzoquinolines derivatives with antimicrobial activity.

Scheme 2

Reaction pathways to obtain benzo[f]quinoline salts 3a–o and cycloadducts 4e and 4g.

Figure 1

PDB structures of targeted molecules represented as ribbons in gold orange (atoms are not displayed): (a) ATP synthase structure; (b) ATP synthase outer membrane region; (c) Topoisomerase II.

Figure 2

ATP synthase with ligands: (a) “native”, crystallographic determined structure; (b) redocked ligand (DNA string).

Figure 3

Total energy (in eV) of the receptor-ligand in BQS 3a–o salts derivative complexes with ATP synthase.

Figure 4

The hydrogen bond energy between ligand and binding pocket aminoacids (in eV) in BQS 3a–o salt derivative complexes with ATP synthase.

Figure 5

Compound 3f is represented in complex with ATP synthase as sticks. Surrounding aminoacids at the binding site are represented as ribbons colored by chain type. Also, a schematic view of the binding site pocket is represented.

Figure 6

BQS 3a–o salts in complex with TOPO II: energies of complexes.

Figure 7

The hydrogen bond energy (in eV) between ligand and binding pocket aminoacids in BQS 3a–o salts derivates complexes with TOPO II.

Figure 8

Compound 3j is represented in complex with TOPO II as sticks. Surrounding aminoacids at the binding site are represented as ribbons colored by chain type. Also, a schematic view of the binding pocket is represented.

Figure 9

Ciprofloxacin in complex with: (a) ATP synthase where hydrogen bond is formed between an OH group and Phe 60; (b) TOPO II, where hydrogen bonds are formed between OH groups and Lys 38, Arg 28, Gly 169, and Ile 170, respectively.

Figure 10

3i and 3n in complex with ATP synthase and TOPO II in their binding pockets: (a) 3i in complex with ATP synthase arene hydrogen bonds are formed between aromatic core and Ala 366, Glu 62, Thr 228, and Gln 58 accept electrons from aromatic and aliphatic carbons; (b) 3i in complex with TOPO II, nitrogen atom interacts with Asp 508 and Glu 433, heterocyclic aromatic carbon share electrons with Asp 508 and Glu 433; (c) 3n in complex with ATP synthase, arene hydrogen bonds are formed between an aromatic core and Tyr 25 and between heterocycle aromatic core and Ala 356; also keto group shares electrons with Arg 357; (d) 3n in complex with TOPO II, arene hydrogen bonds are formed between each heterocyclic aromatic core and His 76, Pro 75, and Tyr 118, respectively.

Scheme 3

Chemical Structures of compounds 3a–o.