Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids.

Emmy Tuenter,Luc Pieters,Sang Sung,Johan Viaene,Paul Cos,Karen Segers,Yvan Heyden,Louis Maes,Kyo Kang

doi:10.3390/molecules22020224

Abstract

Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14-, or 15-membered ring. The ring system consists of a hydroxystyrylamine moiety, an amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, comprised of one or two more amino acid moieties. In vitro antiplasmodial activity was shown before for several compounds belonging to this class, and in this paper the antiplasmodial and cytotoxic activities of ten more cyclopeptide alkaloids are reported. Combining these results and the IC50 values that were reported by our group previously, a library consisting of 19 cyclopeptide alkaloids was created. A qualitative SAR (structure-activity relationship) study indicated that a 13-membered macrocyclic ring is preferable over a 14-membered one. Furthermore, the presence of a β-hydroxy proline moiety could correlate with higher antiplasmodial activity, and methoxylation (or, to a lesser extent, hydroxylation) of the styrylamine moiety could be important for displaying antiplasmodial activity. In addition, QSAR (quantitative structure-activity relationship) models were developed, using PLS (partial least squares regression) and MLR (multiple linear regression). On the one hand, these models allow for the indication of the most important descriptors (molecular properties) responsible for the antiplasmodial activity. Additionally, predictions made for interesting structures did not contradict the expectations raised in the qualitative SAR study.

Highlights

With an estimated amount of 214 million new cases in 2015, malaria is still one of the most important infectious parasitic diseases worldwide [1]
The highest antiplasmodial activity was found for spinanine-B (3), with an IC50 value of 2.1 μM and without cytotoxic effects in concentrations of 64.0 μM or less
14-membered cyclopeptide alkaloidsP.comprised a β-hydroxy phenylalanine (19) or a β-hydroxy leucine (9) showed promising antiplasmodial activities. These results indicate that a β-hydroxy proline moiety is not crucial for displaying antiplasmodial activity

Summary

Introduction

With an estimated amount of 214 million new cases in 2015, malaria is still one of the most important infectious parasitic diseases worldwide [1]. Because of increasing resistance against the currently available antimalarial drugs, there is a compelling need for new therapeutic agents. It is well-recognized that plants are interesting sources for identifying new lead compounds [2], which is well-exemplified by the alkaloid quinine or the terpene artemisinine. This manuscript focuses on a particular subclass of alkaloids, namely the cyclopeptide alkaloids. The ring consists of a hydroxystyrylamine moiety, a typical amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, usually comprised of one or two more amino acid moieties Their basic character is related to the N-atom of the terminal amino acid moiety in the side chain; in some cases a cinnamoyl instead of an amino acid moiety is present, and this type of cyclopeptide alkaloid is referred to as a “neutral cyclopeptide alkaloid”

Methods

Results

Conclusion