β-Carboline: a privileged scaffold from nature for potential antimalarial activity

Abstract

Malaria is one of the most prevalent infectious diseases in the world. Despite the implementation of malaria prophylaxis by the WHO, the mortality rate has been rising. Owing to the development of resistance to presently prescribed antimalarial medication regimes in humans and insecticides in malaria vectors, the prevention and treatment of these illnesses are severely hindered. β-Carbolines are a class of naturally occurring alkaloids that have garnered attention because of their unique structures and diverse biological activities. This review consolidates various methods for synthesizing diverse β-carbolines and highlights their potential as antimalarial agents, emphasizing the molecular targets of Plasmodium falciparum. Based on various research findings, we underscore the potential of β-carbolines to overcome therapeutic challenges and develop effective antimalarials. This review also highlights the structure-activity relationships (SARs) of various β-carboline derivatives to enhance their antimalarial efficacy. With thorough compilation of recent advancements, this review aims to inform and inspire further research and innovation in the quest to combat malaria.

Fig. 1. Potential antimalarial targets of β-carbolines.

Fig. 2. Regioisomers of carbolines.

Scheme 1. The mechanism of the Pictet–Spengler reaction.

Scheme 2. Methods of synthesis of β-carboline.

Fig. 3. Structures of manzamine A, manzamine-A-N-oxide, and 8-hydroxy manzamine.

Fig. 4. β-Carboline analogs as proposed ferredoxin NADP⁺ reductase inhibitors.

Scheme 3. IspD catalyzed step of the methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis in the malaria parasite.

Fig. 5. Structure of MMV008138 and its SAR.

Fig. 6. SAR trends in tetrahydro β-carboline derivatives with potent compounds in the Plasmodium growth inhibition assay.

Fig. 7. Tetrahydro β-carboline derivatives as PfIspD inhibitors.

Fig. 8. SAR of the tetrahydro β-carboline methyl ester with the most active compound in the series.

Fig. 9. SAR of N-aminoalkyl-β-carboline-3-carboxamides with the most active compounds in the series.

Fig. 10. Structures of harmine and harmalol.

Fig. 11. SAR of β carboline–ferrocene hybrids.

Fig. 12. Harmine analogs as PfHSP90 inhibitors.

Fig. 13. SAR of 1-phenyl-6-chloro tetrahydro-β-carboline and the most potent compound in the series.

Fig. 14. SAR of N-9 substituted harmicines with an amide linker and the most active compounds of the series in the Pf growth inhibition assay.

Fig. 15. Structure of harmine analogs and the most active compounds of the series in the Pf growth inhibition assay.

Fig. 16. N-protected tetrahydro-β-carbolines with the most active compounds of the series in the Pf growth inhibition assay.

Fig. 17. SAR trends of manzamine A.

Fig. 18. Structure of 1-amino-6-halo-β-carboline derivatives with the most active compounds of the series in the Pf growth inhibition assay.

Fig. 19. Pyridoxal-β-carboline hybrids and activity of their geometric isomers in the Pf growth inhibition assay.

Fig. 20. C-1 substituted β-carboline-3-carboxamides with the most active compound of the series in the Pf growth inhibition assay.

Fig. 21. SAR of spirotetrahydro-β-carbolines and β-carbolinium cations and the most active compounds of the series in the Pf growth inhibition assay.

Fig. 22. Structure of spirotetrahydro-β-carboline (NITD609) as a probable ATPase 4 inhibitor.

Fig. 23. Manzamine A analog with the most active compound in the Pf growth inhibition assay.

Fig. 24. Structural–activity relationship of β-carboline and tetrahydro-β-carbolines.

Fig. 25. Metabolic pathway of β-carboline derivatives.