The Synthesis and Biological Evaluation of 2-(1 H-Indol-3-yl)quinazolin-4(3 H)-One Derivatives

Abstract

The treatment of many bacterial diseases remains a significant problem due to the increasing antibiotic resistance of their infectious agents. Among others, this is related to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) and Mycobacterium tuberculosis. In the present article, we report on antibacterial compounds with activity against both S. aureus and MRSA. A straightforward approach to 2-(1H-indol-3-yl)quinazolin-4(3H)-one and their analogues was developed. Their structural and functional relationships were also considered. The antimicrobial activity of the synthesized compounds against Mycobacterium tuberculosis H₃₇Rv, S. aureus ATCC 25923, MRSA ATCC 43300, Candida albicans ATCC 10231, and their role in the inhibition of the biofilm formation of S. aureus were reported. 2-(5-Iodo-1H-indol-3-yl)quinazolin-4(3H)-one (3k) showed a low minimum inhibitory concentration (MIC) of 0.98 μg/mL against MRSA. The synthesized compounds were assessed via molecular docking for their ability to bind long RSH (RelA/SpoT homolog) proteins using mycobacterial and streptococcal (p)ppGpp synthetase structures as models. The cytotoxic activity of some synthesized compounds was studied. Compounds 3c, f, g, k, r, and 3z displayed significant antiproliferative activities against all the cancer cell lines tested. Indolylquinazolinones 3b, 3e, and 3g showed a preferential suppression of the growth of rapidly dividing A549 cells compared to slower growing fibroblasts of non-tumor etiology.

Keywords: Mycobacterium smegmatis; antibacterial activity; azaheterocycle; indole; molecular docking; quinazolinone; resistance.

Figure 1

Selected examples of biological active quinazolinone derivatives.

Scheme 1

The key results of optimization of conditions for the model cyclocondensation reaction.

Scheme 2

The synthesis of substituted indolylquinazolinones 3. ^a All reactions were performed at 1.3 mmol scale of aldehyde 1 and 1.3 mmol of amide 2. Isolated yields. ^b The reaction was performed at 3 mmol of aldehyde 1 and 3 mmol of amide 2. Isolated yield. ^c The 2-(1H-indol-3-yl)quinazolin-4(3H)-one (3a) was isolated in 80–96% yield (n.d.—not detected). ^d The formation of indolylquinazolinones 3m, n were detected using thin-layer chromatography (TLC) and gas chromatography–mass spectrometry (GC/MS). The quinazolinone 5a was isolated in 37% and 59% yields. ^e The formation of indole (4a) was determined using TLC and GC/MS. ^f The corresponding N,N-dimethyl-1H-indole-3-carbothioamide (7a) was also isolated in a 21–50% yield. ^g The reaction conditions: aldehyde 1 (0.76 mmol), amide 2 (0.69 mmol), DMSO (1 mL), 100 °C, 3.5 h. Isolated yield. ^h The reaction conditions: aldehyde 1 (0.25 mmol), amide 2 (0.25 mmol), TFA (0.25 mmol), toluene (2 mL), reflux, 40 h.

Scheme 3

The functionalization of the N-atom of model indolylquinazolinone 3a.

Scheme 4

The functionalization of the amide moiety of model indolylquinazolinone 3a.

Figure 2

Influence of sublethal concentrations of amikacin (a) and 2-(5-iodo-1H-indol-3-yl)quinazolin-4(3H)-one (3k) (b) on the S. aureus ATCC 25923 biofilm biomass (OD570) and the number of colony-forming units (CFU) in plankton. Diagrams show the mean values of three (a) and four (b) experiments.

Figure 3

In vitro cytotoxicity of the compounds 3b, 3d–3g, k, and 3r to cells MCF7′, A549, HEK293T, and VA13 via MTT assay.

Figure 4

Best energy interactions between ligands and Rel_Seq protein synthetic domain active site. (a) Reference ligand indole-5-carboxylic acid; (b) 3o compound; and (c) 3ab compound. Protein chains are shown in grey thin sticks, ligands are shown in blue thick sticks, interactions are shown in dashed lines: yellow hydrogen bonds, blue pi–pi stacking and green pi-cation interactions, purple salt bridges.

Figure 5

Best energy interactions between ligands and Rel_Mtb protein synthetic domain active site. (a) 3b compound, (b) 3ab compound, and (c) 3p compound. Color coding is identical to Figure 4.