Tryptanthrin from microwave-assisted reduction of isatin using solid-state-supported sodium borohydride: DFT calculations, molecular docking and evaluation of its analgesic and anti-inflammatory activity

Abstract

Tryptanthrin is a potent natural alkaloid with good in vitro pharmacological properties. Herein, we report the synthesis of the compound via a new method involving the reduction of isatin with solid-state-supported sodium borohydride under microwave irradiation. The title compound has been tested for its analgesic and anti-inflammatory activity. The results showed that tryptanthrin dose dependently inhibits oedema and pain formation in all the models used. The agent also exhibited significant higher effects in its anti-inflammatory and analgesic activities better than positive drugs (aspirin and indomethacin) being currently used in the treatment and in the management of acute and chronic forms of pain and inflammatory disorders. The inhibitory potential of the compound was investigated by molecular docking using the software AutoDock Vina. The docking results were used to better rationalize the action and prediction of the binding affinity of tryptanthrin. Density Functional Theory (DFT) calculations at the B3LYP/6-311++G (2df, 2pd) level of theory showed that compared to ascorbic acid, tryptanthrin shows higher antioxidant activity which may be improved upon by functionalizing the aromatic core to enhance its solubility in polar solvents. The calculated electronic and thermodynamic properties obtained for tryptanthrin compete well with the standard ascorbic acid.

Keywords: Analgesic and anti-inflammatory activity; Borohydride reduction; DFT calculations; Isatin; Molecular docking; Tryptanthrin.

Scheme 1

Synthetic routes to tryptanthrin and its atom numbering.

Figure 1

(a) Optimized structure of tryptanthrin (I_oxi) (b) Four-electron oxidized/reduced forms of catechol (II) (c)Reduced form of tryptanthrin (I_red)

Scheme 2

Isodesmic redox-conversion of compound (I) by catechol (II).

Scheme 3

Thermodynamic cycle employed to obtain compound I redox potential.

Scheme 4

Isodesmic redox-conversion of ascorbic acid (AA) by catechol (II).

Scheme 5

Sodium borohydride reduction of some substituted indole-2,3-dione (isatin) [57, 58].

Scheme 6

Possible rationalization of sodium borohydride reduction of isatin to tryptanthrin

Figure 2

(a) Cartoon rendering of the protein showing tryptanthrin overlapping with heme in the same site. (b) Cartoon rendering of the protein showing the flexible residues at the S58 binding site adjacent to the site where heme occupies in the protein. (c) A surface rendering of the protein showing tryptanthrin lodged in the pocket that seats the heme (without the heme). (d) Another surface rendering showing the tryptanthrin overlapped with the heme in the heme pocket.

Figure 3

Calculated electronic absorption spectrum of tryptanthrin

Figure 4

Molecular orbital energy levels of tryptanthrin

Figure 5

Molecular orbital symmetries corresponding to the different molecular energy levels of tryptanthrin