Evaluation of Antimicrobial, Anticholinesterase Potential of Indole Derivatives and Unexpectedly Synthesized Novel Benzodiazine: Characterization, DFT and Hirshfeld Charge Analysis

Abstract

The pharmacological effectiveness of indoles, benzoxazepines and benzodiazepines initiated our synthesis of indole fused benoxazepine/benzodiazepine heterocycles, along with enhanced biological usefulness of the fused rings. Activated indoles 5, 6 and 7 were synthesized using modified Bischler indole synthesis rearrangement. Indole 5 was substituted with the trichloroacetyl group at the C⁷ position, yielding 8, exclusively due to the increased nucleophilic character of C⁷. When trichloroacylated indole 8 was treated with basified ethanol or excess amminia, indole acid 9 and amide 10 were yielded, respectively. Indole amide 10 was expected to give indole fused benoxazepine/benzodiazepine 11a/11b on treatment with alpha halo ester followed by a coupling agent, but when the reaction was tried, an unexpectedly rearranged novel product, 1,3-bezodiazine 12, was obtained. The synthetic compounds were screened for anticholinesterase and antibacterial potential; results showed all products to be very important candidates for both activities, and their potential can be explored further. In addition, 1,3-bezodiazine 12 was explored by DFT studies, Hirshfeld surface charge analysis and structural insight to obrain a good picture of the structure and reactivity of the products for the design of derivatised drugs from the novel compound.

Keywords: DFT; anticholinesterase; antimicrobial; benzodiazine; indole; novel benzodiazine.

Scheme 1

Retrosynthesis of indole-based benzodiazepine/benzoxazepine.

Scheme 2

Reagents and conditions: (a) PhNH₂, AcOH or NaHCO₃ (LiBr) reflux in EtOH; (b) Cl₃CCOCl_, CH₂Cl₂, reflux; (c) aq KOH in EtOH; (d) aq NH₃, reflux; (e) NaH in DMSO (solid arrow), MeCH(Br)CO₂Me (arrow with dashed lines).

Figure 1

The ORTEP presentation of 8 formed at a probability level of 50%. Hollow circles represent H-atoms (black balls shows carbon atoms, red balls show oxygen, while blue and green show nitrogen and chloride, respectively).

Scheme 3

LR EIMS fragmentation of 9.

Figure 2

A portion of ESI MS of 12 showing (M + H)^+•.

Figure 3

The ORTEP presentation of 12 formed at a probability level of 50%. Hollow circles represent H-atoms (black balls shows carbon atoms, red balls show oxygen, while blue show nitrogen).

Figure 4

Optimized geometries of compounds (10) and (12) at PBE0-D3BJ/def2-TZVP level of theory. In 3D models, red represents oxygen, grey carbon, and blue nitrogen atoms. Hydrogen atoms are omitted for clarity. (Grey balls shows carbon atoms, red balls show oxygen, while show nitrogen).

Figure 5

Iso-surface lots of frontier molecular orbitals of compound (10).

Figure 6

Graphical illustration of π$\cdots$π stacking interaction in the supramolecular assembly of 8. For clarity, H-atoms are not displayed.

Figure 7

Packing diagram of 12 showing infinite chain formed by H-bonding. For clarity, selected H-atoms are displayed.

Figure 8

Graphical illustration of π$\cdots$π stacking and C-H⋯π interaction in the supramolecular assembly of 12. For clarity, H-atoms are not displayed.

Figure 9

Hirshfeld surface plotted over for (a) 8 in the range −0.1019 to 1.4971 a.u, (b) 12 in the range −0.1593 to 1.8443 a.u.

Figure 10

Important 2D plots for (a–d) 8, (e–h) 12 (Figure S10).

Figure 11

Graphical view of voids along the b-axis for (a) LR-III92A, (b) LR-III-9730_0m.

Figure 12

Ligand protein interactions for the proposed compounds (5–10, 12). The right panels show the ligand interactions in the binding pocket (prepared using PyMol), while the left panels show H bonding and hydrophobic interactions.

Figure 12

Ligand protein interactions for the proposed compounds (5–10, 12). The right panels show the ligand interactions in the binding pocket (prepared using PyMol), while the left panels show H bonding and hydrophobic interactions.