Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

Abstract

Indole derivatives have been the focus of many researchers in the study of pharmaceutical compounds for many years. Researchers have investigated the effect of carboxamide moiety at positions 2 and 3, giving unique inhibitory properties to these compounds. The presence of carboxamide moiety in indole derivatives causes hydrogen bonds with a variety of enzymes and proteins, which in many cases, inhibits their activity. In this review, synthetic strategies of indole 2 and 3-carboxamide derivatives, the type, and mode of interaction of these derivatives against HLGP, HIV-1, renin enzyme, and structure-activity studies of these compounds were investigated. It is hoped that indole scaffolds will be tested in the future for maximum activity in pharmacological compounds.

Keywords: Carboxamide moiety; HIV-1; HLGP; Indole; Inhibitory activity; Renin.

Fig. 1

Numbering order of the indole molecule

Fig. 2

Synthetic routes for derivatives of indole 2-carboxamide (molecules 10–20), indole 3-carboxamide (molecules 25–28)

Fig. 3

Structure of molecule 2, (*) inhibitor sites

Fig. 4

The interaction of the HLGPa with the molecule 2 through the new allosteric binding sites [44]

Fig. 5

The interacting mode of compound 6 with HLGP [47]

Fig. 6

Structure of compound 15 (synthesized according to the route e)

Fig. 7

Crystallographic analysis diagram of the interactions made by compound 16 with HLGP [26]

Fig. 8

Structure of compound 21 (synthesized according to the route e)

Fig. 9

Predicted binding model for compound 21 (R-isomer) with HLGP [25]

Fig. 10

Structure of compound 22 (synthesized according to the routes a and b)

Fig. 11

Structure of compound 23 (synthesized according to the route c)

Fig. 12

Graphical result of the dockings of reference compound 22 into 14 RTs [52]. Conformations docked in the different RTs are color-coded

Fig. 13

Structure of compounds 24 and 25 (synthesized according to the route d)

Fig. 14

Structure of compounds 26–29

Fig. 15

X-ray crystal structures of two indole-3-carboxamides 31 and 32 in complex with human renin, (synthesized according to the route k) [32]

Fig. 16

X-ray crystal structure of compound 33 in complex with human renin, (synthesized according to the route k) [32]

Fig. 17

Interaction plots of a electrostatic, b steric and c hydrophobic of renin enzyme and indole 3-carboxamide derivatives [61]