Synthesis, characterization, DFT calculations, comparative in vitro and in silico screening of anti-bacterial, anti-urease and α-amylase inhibition activities of indole derivatives with hirshfeld surface analysis and crystal structure explorations of Bis(4,6-dimethoxy-2,3-diphenyl-1H-7,7΄-indolylmethane

Abstract

• The study involved synthesis, characterization, crystal data investigation, DFT Calculations, and Hirshfeld Surface Analysis of compound 4 (code lr_iii_64_0m). • Anti-bacterial, α-amylase and anti-urease activities of Bis (4,6-dimethoxy-2,3-diphenyl-1H-7,7΄-indolylmethane 1–4 was evaluated. • Single crystal XRD analysis was used to verify the structure of synthesized compound 4 (code lr_iii_64_0m). • DFT studies are performed for the evaluation of HOMO, LUMO, reactivity, stability, electronegativity, and chemical potential of the differently substituted rings. • In silico anti-bacterial, anti-urease and α-amylase activities of these synthesized indole derivatives and dimerized indol derivatives displayed promising therapeutic potential. This work involves synthesis, characterization, crystal data investigation, DFT Calculations, Hirshfeld Surface Analysis, anti-urease and anti-bacterial activities of Bis(4,6-dimethoxy-2,3-diphenyl-1H-7,7΄-indolylmethane. Modified Bishler Indole synthesis was used to synthesize indole 1 , which, upon formylation, yielded 2 . The mild reducing agent NaBH 4 was used to reduce formylated indole 2 affording indole alcohol ( 3) with good yield. Coupling alcohol 3 with various coupling agents, such as, (MeO) 2 CO, α-haloacid halides or (COCl) 2 , was expected to produce heterocyclic ring 5 . Coupling agents were expected to facilitate the intramolecular cyclization in indole alcohol 3 to yield indole fused oxazepine ring 5 . However, all the above acidic conditions resulted in the formation of bis indole 4 [lr_iii_64_0m] (methylene bridge between two indolic moieties) in good yield. Several spectroscopic techniques, such as UV–Visible spectroscopy, 13 CNMR, 1 HNMR, and IR, were used to analyze the synthesized compounds. Single crystal XRD analysis was used to verify the structure of 4 [lr_iii_64_0m]. The configuration of the molecule was described by checking the planarity of the various groups and the dihedral angles between them. Weak intermolecular interactions stabilized the supramolecular assembly; these interactions were examined using Hirshfeld surface analysis to determine interatomic contacts. To determine which contact has a greater potential to establish interactions within crystal packing, enrichment ratios are computed. The analysis of voids anticipated how crystal would respond to external stress. DFT studies are performed for the evaluation of HOMO, LUMO, reactivity, stability, electronegativity, chemical potential, electrophilicity, electronic distribution, nucleophilic and electrophilic behaviors of the differently substituted rings. These studies can unfold many aspects of chemical behaviors and may be helpful for the prediction of possible chemical reactions and interactions as reactants or with receptors in medicines. In vitro and in silico antibacterial, antiurease and α-amylase activities of these synthesized indole derivatives and dimerized indole showed the potency of indole derivatives.

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