Elsevier

Bioorganic & Medicinal Chemistry

Volume 19, Issue 17, 1 September 2011, Pages 5199-5206
Bioorganic & Medicinal Chemistry

Synthesis and antimalarial evaluation of novel benzopyrano[4,3-b]benzopyran derivatives

https://doi.org/10.1016/j.bmc.2011.07.009Get rights and content

Abstract

7-Methoxyflavenes and 5,7,8-trimethoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate the benzopyrano[4,3-b]benzopyran ring system present in the natural product, dependensin. Dependensin and its analogs were subjected to antimalarial growth inhibition assays against Plasmodium falciparum and found to have IC50 values ranging between 1.9 and 3.9 μM.

Introduction

Flavonoids are a group of heterocyclic polyphenolic compounds widely distributed in the plant kingdom. They occur naturally in fruits, vegetables, nuts, seeds and flowers and form a significant part of our daily diet.1 Flavonoids are known to display a diverse range of biological and pharmacological activities.1 For example, baicalein, oroxylin A and wogonin, the three major flavonoids isolated from Scutellaria baicalensis, a traditional Chinese herb are well noted for their broad spectrum of biological activities, in particular for their antioxidant properties.2

Biflavonoids are comprised of two identical or non-identical flavonoid units, joined symmetrically or unsymmetrically through linkers of varying lengths. The large number of possibilities in the length, position and type of linkages, as well as in the number and nature of substituents, gives rise to an enormous structural diversity to the biflavonoids class.3 Biflavonoids have received increasing recognition due to their wide spectrum of pharmacological properties, including anticancer, antiinflammatory, antimicrobial, antiviral, and anticlotting activities.3

Despite their promising biological activities, the development of biflavonoids as therapeutic agents has been hampered by their low abundance in nature, tedious extraction and purification procedures, and limited biological data of the biflavonoids class. Therefore, it is highly desirable to develop efficient synthetic methodologies, which could generate not only the natural products themselves but also their synthetic analogs for pharmacological applications.

Dependensin 1 is a dimeric flavonoid isolated from the root bark of a Tanzanian medicinal plant, Uvaria dependens. The crude extract of this plant shows potent antimalarial activity.4 It is well-known that malaria constitutes a major health problem in tropical and sub-tropical regions of the world, with 200–350 million cases annually and mortality reaching 1 million, particularly among children in sub-Saharan Africa.5 Malaria is caused by protozoan parasites of the phylum Apicomplexa, which are transmitted by blood feeding Anopheline mosquitoes. There are four main human malaria parasites, that is, Plasmodium ovale, Plasmodium malaria, Plasmodium vivax and Plasmodium falciparum, with the latter two being responsible for the majority of malaria cases worldwide. P. falciparum, the most virulent of the four main species infecting humans, has become resistant to nearly all currently employed antimalarial drugs used for prophylaxis and treatment.6 Even artemisinin combination therapy (ACT), the current first treatment for drug-resistant P. falciparum malaria is now under threat.7

First cases of resistance against P. falciparum were reported in the 1970s against the popular antimalarials chloroquine and sufadoxine-pyrimethamine, barely 10 years after these drugs were introduced for the treatment of malaria. Chloroquine has also been the therapy of choice for the treatment of blood stage vivax malaria, but chloroquine resistance in P. vivax has developed since the nineties of the last century. Besides the increasing drug resistance in plasmodia strains worldwide, an effective drug employment is hampered by high costs and major side effects of other antimalarials like mefloquine or atovaquone.6

These developments emphasize the need for new strategies in combating the tropical disease. Hence, our research group is addressing the need to develop new drugs. Here, we present data on the development of efficient synthetic methodologies to dependensin and its analogs, as potential new lead antimalarial compounds.

The unique heterocyclic ring system present in dependensin contains a dense array of functionality and stereochemistry, which includes two-fused benzopyran rings, four stereocenters and one trans double bond.4

Nkunya et al. proposed that the natural product, dependensin originated from the acid-catalyzed reaction of the corresponding flavene, 5,7,8-trimethoxyflav-3-ene, but were unable to verify it experimentally, obtaining a ring-opened compound instead.4 However, the successful synthesis of dependensin via the acid-catalyzed reaction of 5,7,8-trimethoxyflavene has been recently reported by our research group.8 We have also previously shown that the benzopyrano[4,3-b]benzopyran ring system present in dependensin could be synthesized via the acid-catalyzed dimerization reaction of 4′,7-diacetoxyflav-3-ene.8 Similar acid-catalyzed reactions of the corresponding 4′,5-diacetoxy- and 4′,6-diacetoxyflavenes produced a complex mixture of products.8

Encouraged by these results, we targeted the acid-catalyzed reactions of 7-methoxyflavenes and 5,7,8-trimethoxyflavenes to generate novel dependensin analogs for biological applications. Interestingly, we found that the dimerization products obtained were dependent on the position of the methoxy group in the flavene nucleus. We have also recently reported the synthesis of biflavonoids containing a new ring system, a tetrahydrochromeno[2,3-b]chromene, generated via the acid-catalyzed reactions of 5-methoxy- and 6-methoxyflavenes.9

We report herein the facile one step methodology to the synthesis of a series of highly functionalized benzopyrano[4,3-b]benzopyrans from the acid-catalyzed reactions of 7-methoxyflavenes and 5,7,8-trimethoxyflavenes along with their antimalarial inhibition assay results.

Section snippets

Synthesis of 7-methoxyflavenes

Flavenes are direct precursors to the dimeric flavonoids and therefore, an efficient route to their synthesis was considered highly desirable for this study. The base catalyzed condensation of hydroxyacetophenones with aldehydes to generate chalcones has been commonly employed,10 which has been followed by cyclization in the presence of strong acids to furnish flavanones in typically low yields.10 Alternatively, intramolecular oxidative cyclization of chalcones with I2/DMSO could yield the

Conclusion

A facile simple one step methodology to the synthesis of a series of novel benzopyrano[4,3-b]benzopyrans has been developed via the acid-catalyzed dimerization reactions of 7-methoxyflavenes and 5,7,8-trimethoxyflavenes. Moderate antimalarial activity coupled with synthetic tractability of several synthetic bisflavonoids suggests that this structure class may warrant further investigation as potential antimalarial agents.

Materials and methods

All reagents and solvents were obtained from commercial sources and purified if necessary. Melting points were measured using a Mel-Temp melting point apparatus and are uncorrected. Microanalyses were performed on a Carlo Erba Elemental Analyser EA 1108 at the Campbell Microanalytical Laboratory, University of Otago, New Zealand. 1H and 13C NMR spectra were obtained on Bruker DPX300 (300 MHz). Mass spectra were recorded on either a Bruker FT-ICR MS (EI) or a Micromass ZQ2000 (ESI). Infrared

Acknowledgments

We thank the University of New South Wales, and the Australian Research Council (ARC) for Linkage Project (LP0455373) funding to N.K. and D.B., and Future Fellowship funding to K.T.A., and the Australian Red Cross Blood Service for providing human blood and sera for P. falciparum culture.

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