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α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
University of Florida, College of Medicine, Biochemistry and Molecular Biology.
Hospital Clínico de Santiago de Compostela, Fundación Pública Galega de Medicina Xenómica.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 16, 5933-5949 p.Article in journal (Refereed) Published
Abstract [en]

The impact of moving the P1 side-chain from the β-position to the α-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising α-benzylnorstatines and α-phenylnorstatines. Twelve α-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired α-substituted norstatines as pure stereoisomers. The best compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nm in PM4 from P. ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to P. falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding affinities using the linear interaction energy method (LIE).

Place, publisher, year, edition, pages
2009. Vol. 17, no 16, 5933-5949 p.
Keyword [en]
malaria, plasmepsin, inhibitors, microwave-assisted synthesis, molecular dynamics, Linear interaction energy mehtod
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-100961DOI: 10.1016/j.bmc.2009.06.065ISI: 000268762900020OAI: oai:DiVA.org:uu-100961DiVA: diva2:211424
Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2014-05-08Bibliographically approved
In thesis
1. On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry
Open this publication in new window or tab >>On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics.

In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases.

Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes.

In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 109 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 100
microwave-assisted chemistry, malaria, aspartic protease, plasmepsin, PfPM4, PmPM4, PoPM4, PvPM4, inhibitor, unsaturated lactone, unsaturated lactam, unsaturated amide, lactam, Bestmann's ylide, ionic liquid, polymerase chain reaction, thermophilic enzyme
National Category
Medicinal Chemistry Organic Chemistry Biochemistry and Molecular Biology
Research subject
urn:nbn:se:uu:diva-101356 (URN)978-91-554-7535-2 (ISBN)
Public defence
2009-06-12, B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Available from: 2009-05-20 Created: 2009-04-23 Last updated: 2009-05-20Bibliographically approved

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Gutiérrez-de-Terán, HugoLarhed, Mats
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