Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents

Abstract

The condensation of phthalic anhydride afforded structurally modified isoindoline-1,3-dione derivatives with selected amino-containing compounds. The title compounds (2-30) have been characterized by thin-layer chromatography (TLC), infrared spectroscopy, ¹H and ¹³C NMR spectroscopy, and mass spectroscopy. All of the compounds were assessed for their antimycobacterial activity toward the H37Rv strain by a dual read-out assay method. Among the synthesized compounds, compound 27 possessed a significant IC₅₀ of 18 μM, making it the most potent compound of the series. The InhA inhibitory (IC₅₀) activity of compound 27 was 8.65 μM in comparison to Triclosan (1.32 μM). Computational studies like density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. A quantum-mechanics-based DFT study was carried out to investigate the molecular and electronic properties, reactivities, and nature of bonding present in the synthesized compounds and theoretical vibrational (IR) and isotropic value (¹H and ¹³C NMR) calculations.

Figure 1

Reported isoindoline-1,3-dione derivatives.

Scheme 1

Reagents and conditions: 0.1 mol of the primary amino group containing alicyclic compound, 0.1 mol of phthalic anhydride in 50–75 mL of glacial acetic acid, reflux for 3 h; (a) 4-fluoroaniline, (b) 2-methylaniline, (c) 3-chloro-4-fluoroaniline, (d) 3-methylaniline, (e) 4-chloroaniline, (f) 3-chloroaniline, (g) 4-bromoaniline, (h) 2-bromoaniline, (i) 3-nitroaniline, (j) glycine, (k) 4-methylpyridin-2-amine, (l) 5-methylpyridin-2-amine, (m) 5-bromopyridin-2-amine, (n) 5-amino-2-hydroxybenzoic acid.

Scheme 2

Reagents and conditions: 0.1 mol of the primary amino group containing alicyclic compound, 0.1 mol of phthalic anhydride in 50–75 mL of glacial acetic acid, reflux for 3 h; (a) 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine, (b) 5-(4-chlorophenyl)-1,3,4-thiadiazol-2-amine, (c) 5-(2-chlorophenyl)-1,3,4-thiadiazol-2-amine, (d) 5-phenyl-1,3,4-thiadiazol-2-amine, (e) 5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine, (f) 5-(3-bromophenyl)-1,3,4-thiadiazol-2-amine, (g) 5-(3-methoxyphenyl)-1,3,4-thiadiazol-2-amine, (h) 5-(3-methylphenyl)-1,3,4-thiadiazol-2-amine, (i) 5-benzyl-1,3,4-thiadiazol-2-amine, (j) 5-(2-fluorophenyl)-1,3,4-thiadiazol-2-amine, (k) 5-(3-chlorophenyl)-1,3,4-thiadiazol-2-amine, (l) 5-(4-iodophenyl)-1,3,4-thiadiazol-2-amine, (m) 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-amine, (n) 5-methyl-1,3,4-thiadiazol-2-amine, (o) 8-amino-4-methyl-2H-chromen-2-one.

Figure 2

Linear regression between experimental and calculated wavenumbers for compound 14.

Figure 3

Experimental and theoretical IR spectra of compound 14.

Figure 4

Analysis of the linear relationship between experimental and calculated chemical shifts (¹H NMR) for compound 14.

Figure 5

¹H NMR spectrum of compound 14.

Figure 6

Linear regression between experimental and calculated chemical shifts (¹³C NMR) for compound 14.

Figure 7

¹³C NMR spectrum of compound 14.

Figure 8

Structure–activity relationship of isoindoline-1,3-diones (2–30).

Figure 9

(A) Docking validation; (B, C) binding pose of compound 5 with InhA; (D, E) binding interaction of compound 6 with InhA.

Figure 10

(A, B) Binding pose of compound 11 with InhA; (C, D) binding interaction of compound 27 with InhA.

Figure 11

DFT-based frontier molecular orbital energies calculations of HOMO, LUMO, and maximum electrostatic potential (MESP).

Figure 12

(A) Protein (InhA) and ligand (compound 27) RMSD; (B) root-mean-square fluctuation (RMSF) of the InhA; (C) different interactions of compound 27 during 100 ns with InhA; (D) interaction fraction of different residues with compound 27 during 100 ns; and (E) ligand (compound 27) properties.

Figure 13

Per residue binding free energy of the InhA with compound 27.

Figure 14

DCCM analysis of compound 27 (D1, D2, and D3 are highly correlated residues of the InhA).

Figure 15

PCA of compound 27.