Understanding Halogen Bonding in Solution

Halogen bonding is an electron density donation-based weak interaction that has so far mostly been investigated in computational and crystallographic studies.

We examine halogen bonding formed in solution environment employing a novel, exceedingly accurate NMR methodology. Using a combination of spectroscopic and computational techniques the energetics of halogen bonds and the role of electrostatic and non-electrostatic effects in the interaction will be studied. Variation of bond length and symmetry as well as their relevance in inter- and intramolecular interactions are being elucidated.

The gained knowledge will be applied to understand the impact of halogen bonding in biological systems, such as protein-ligand and lipide-ligand interactions as well as used to develop new applications of halogen bonding in organic, analytical and pharmaceutical chemistry.

Our work is finacially supported by the Swedish Scientific Research Council, the European Research Council, the Carl Tryggers Foundation, the Åke Wibergs Foundation, the Royal Society of Arts and Sciences in Göteborg, and the Swedish Foundation for Internationalization in Research and Higher Education.

Some recent publications:
Counterion influence on the N-I-N halogen bond
Bedin, M.; Karim, A.; Reitti, M.; Carlsson, A.-C.C., Topic, F.; Cetina, M.; Pan, F.; Havel, V.; Al-Ameri, F.; Sindelar, V.; Rissanen, K.; Gräfenstein, J.; Erdelyi, M. Chem. Sci. 2015, 6, 3746-3756
The nature of [N-Cl-N]+ and [N-F-N]+ halogen bonds in solution
Karim, A.; Reitti, M.; Carlsson, A.-C.C.; Gräfenstein, J.; Erdelyi, M. Chem. Sci. 2014, 5, 3226-3233
Halogen bond symmetry: the N-X-N bond
S. B. Hakkert; M. Erdelyi J. Phys. Org. Chem. 2014, DOI: 10.1002/poc.3325
Mapping the sevoflurane-binding sites of calmodulin
Brath, U.; Lau, K.; Van Petegem, F.; Erdelyi, M. Pharma. Res. Per. 2014, 2, e00025 (DOI: 10.1002/prp2.25)
Halogen Bonding in Solution, Erdelyi, M. Chem. Soc. Rev. 2012, 41, 3547-3557
Symmetric Halogen Bonding is Preferred in Solution, Carlsson, A. C. C.; Gräfenstein, J.; Budnjo, A.; Bergquist, J.; Karim, A.; Kleinmaier, R.; Brath, U.; Erdelyi, M.  J. Am. Chem. Soc. 2012, 134, 5706-5715.
Symmetry of [N-X-N]+ Halogen Bonds in Solution, Carlsson, A.C.C; Gräfenstein, J.; Laurila, J. L.; Bergquist, J.; Erdelyi, M. Chem. Commun. 2012, 48, 1458-1460.
Solvent Effects on Halogen Bond Symmetry Carlssom, A.-C.C., Uhrbom, M., Karim, A., Brath, U., Gräfenstein, J., Erdelyi, M. CrystEngComm., 2013, 15, 3087-3092.

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Exploration of Antimalarial Natural Products from Kenyan Plants

Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major disease in the tropical and subtropical regions of the world. Out of yearly 300 to 500 million clinical episodes, of which 90% occur in tropical sub-Saharan region, 1.5-2.7 million are lethal. Notably, malaria is the leading cause of mortality of children under five years of age and of pregnant women in this area. The emergence of chloroquine-resistant strains of the parasite Plasmodium falciparum and the rising resistance of the vectors (Anopheles spp.) to insecticides in combination with poverty and lack of a well-functioning health care system are the main causes for the increase of malaria morbidity and mortality over the past decade. To date over thousand herbal species are in use in indigenous health systems as means of treating malaria and managing related fever; however, their efficacy and active components have not yet been studied systematically. Although there are several antimalarial drugs on the market, most do not meet the requirement of ≤ 1 USD per treatment and are unaffordable for the majority of Africa. Chloroquine and sulphadoxine-pyrimethamine are the only remedy available for such low price; however, the already widespread and relentlessly increasing resistance against these agents makes them virtually useless. The discovery of Artemisinin from Artemisia annua showed that plants used in traditional medicine may provide new source of lead structures for the development of novel antiplasmodial drugs.

The goal of this ongoing project is identification of novel pharmaceutical lead compounds from the Kenyan flora by evaluation of efficacious traditional remedies by modern techniques.  We collaborate with the research group of Prof. Abiy Yenesew at the University of Nairobi, Kenya, and aim to join our forces by integrating cultural practice with modern pharmaceutical approaches to advance new solutions to malaria, the disease of highest mortality in sub-Saharan Africa. Expected outcomes of the project are bioactive natural products rapidly transferable to the treatment of malaria - either through identification of new lead compounds or through development of phytomedicines.

Some recent publication:
Flemingins G–O, Cytotoxic and Antioxidant Constituents of the Leaves of Flemingia grahamiana
Gumula, I.; Alao, J.P.; Ndiege, I.O.; Sunnerhagen, P.; Yenesew, A.; Erdelyi, M. J. Nat. Prod. 2014, 77, 2060-2067.
Constituents of the roots and leaves of Ekebergia capensis and their potential antiplasmodial and cytotoxic activities
Irungu, B.N.; Orwa, J.A.; Gruhonjic, A.; Fitzpatrick, P.A.; Landberg, G; Kimani, F.; Midiwo, J.; Erdelyi, M.; Yenesew, A. Molecules 2014, 19, 14235-14246.
Cytotoxic Quinones from the roots of Aloe dawei
Negera, A.; Induli, M.; Fitzpatrick, P.; Alao, J. P.; Sunnerhagen, P.; Landberg, G.; Yenesew, A.; Erdelyi, M. Molecules 2014, 19, 3264-3273.
Anthraquinones of the roots of Pentas micrantha
Endale, M.; Ekberg, A; Alao, J. P.; Akala, H.; Ndaka, A.; Sunnerhagen, P.; Erdelyi, M.;  Yenesew, A. Molecules 2013, 18, 311-321.
Busseihydroquinones A-D from the Roots of Pentas bussei
Endale, M.; Ekberg, A; Akala, H.; Alao, J. P.; Sunnerhagen, P.; Yenesew, A.; Erdelyi, M. J. Nat. Prod. 2012, 75, 1299-1304.
Antiplasmodial Quinones from Pentas longiflora and Pentas lanceolata
Endale, M.; Alao, J.P.; Akala, H. M.; Rono, N. K.; Eyase, F. L.; Derese, S.; Ndakala, A.; Mbugua, M.; Walsh, D.S.; Sunnerhagen, P.; Erdelyi, M.; Yenesew, A. Planta Medica 2012, 78, 31.

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Development of Metallo-beta-lactamase Inhibitors to Control Antibiotic Resistance

The appearance of superbugs producing metallo-beta-lactamases (MβLs) have resulted in a clinical crisis.

In this project, subclasses of MβLs including NDM-1 are expressed and purified and a a series of beta-lactam antibiotics transition state analogs are synthesized. Their broad-spectrum inhibition activity and structure-activity relationship is evaluated. Special attention is given to possible synergestic effects when applied in combination with antibiotics for inhibition of antibiotic resistant bacteria. The complexes of MβLs and the transition state analogs are studied by solution NMR and X-ray crystallography, to provide information useful for the development of clinically applicable broad spectrum inhibitors.

The long term goal of this project is to create novel compounds with broad-spectrum inhibitory potency to MβLs and superbugs, and to provide a deeper understanding of molecular processes behind antibiotic action that is expected to support the development of additional antibacterial drugs.