Indole: The After Next Scaffold of Antiplasmodial Agents?

Abstract

Malaria remains a global public health problem due to the uphill fight against the causative Plasmodium parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant Plasmodium strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of Plasmodium through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.

Keywords: PfATP4; antimalarial agents; hemozoin inhibition; indole; multi-target approach.

Figure 1

The chemical structures of quinoline in quinine (1) and chloroquine (2), and the endoperoxide scaffold in (+)-artemisinin (3).

Figure 2

Non-essential structural features in TCMDC-134,281 (4a) which were moved in the design of TCMDC-134,281 (4b).

Figure 3

Chemical structures of dihydrousamabarensine (5a), isosungucine (5b), flinderoles A–C (6a–6c), isoborreverine (7a) and dimethylisoborreverine (7b).

Figure 4

Chemical structures of (1R,3S)-8a and (1S,3R)-8a enantiomers of a spiroazepineindole derivative and cipargamin (8b).

Figure 5

Chemical structures of conjugated indole analogues; (A) The optimal length of the linker connecting the triazolyl or piperazinyl tether to isatin or 3-hydroxyindole various from ethyl to pentyl alkyl in isatin-chloroquine conjugates (9a–9c); (B) Conjugates of indol-3-yl with quinoline (10a) or quinolinium (10b); (C) The chemical structures of cryptolepine (11a), ellipticine (11b) and 2,7-dibromocryptolepine (11c); (D) The chemical structure of tryptanthrin (12a), and its more soluble 3-methyl ester (12b) and 3-chloro (12c) derivatives.

Figure 6

Intercalation into the CG-rich sequence of DNA by cryptolepine (PyMOL was used to regenerate the picture from the crystal structure with PDB accession number 1K9G). Cyan color: cryptolepine (19).

Figure 7

Chemical structures of aminoindole derivatives (13a–13b), indole-3-glyoxyl tyrosine derivatives (14a–14b), prenylated indole alkaloids (15a–15c), and melatonin antagonist (16a–16b).

Figure 8

Homology model of PfATP4 regenerated using the crystal structure of SERCA (PDB 3TLM) as a template.