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Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases: Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.

The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 160
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-172341ISBN: 978-91-554-8345-6 (print)OAI: oai:DiVA.org:uu-172341DiVA: diva2:514061
Public defence
2012-05-25, BMC, B42, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-05-03 Created: 2012-04-04 Last updated: 2018-01-12Bibliographically approved
List of papers
1. A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
Open this publication in new window or tab >>A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
2009 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 7, no 13, 2809-2815 p.Article in journal (Refereed) Published
Abstract [en]

A rapid and versatile one-pot, 2 * 10 min microwave protocol for the prepn. of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones, e.g., I, from the corresponding primary amines and aldehyde was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha -aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta -strand inducing core structures in a medicinal chem. context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-contg. Hepatitis C virus NS3 protease inhibitors, e.g., II, is reported.

National Category
Pharmaceutical Sciences
Research subject
Medicinal Chemistry; Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-110737 (URN)10.1039/b90550lk (DOI)000267124300020 ()
Note

CAN 151:245625 28-17 Heterocyclic Compounds (More Than One Hetero Atom) Journal 1477-0520 written in English. 1178896-10-0P; 1178896-11-1P Role: PAC (Pharmacological activity), SPN (Synthetic preparation), BIOL (Biological study), PREP (Preparation) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 4248-19-5 (tert-Butyl carbamate); 259214-56-7 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 1178896-08-6P; 1178896-09-7P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. and hepatitis C virus NS3 protease inhibitory activity of (pyrazinylacetamido)cyclopropanoic acid derivs. via coupling reaction, hydrolysis, and peptide coupling of pyrazinylacetate deriv.); 62-53-3 (Aniline); 100-46-9 (Benzylamine); 100-52-7 (Benzaldehyde); 108-91-8 (Cyclohexylamine); 109-73-9 (1-Butanamine); 122-78-1 (Benzeneacetaldehyde); 1122-91-4 (4-Bromobenzaldehyde); 2393-23-9 (4-Methoxybenzylamine); 2462-31-9; 3009-97-0; 3010-04-6; 3081-24-1; 3132-99-8 (3-Bromobenzaldehyde); 3182-93-2; 21760-98-5; 37760-98-8 Role: RCT (Reactant), RACT (Reactant or reagent) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.); 2182-39-0P; 252271-82-2P; 308845-80-9P; 1178896-02-0P; 1178896-07-5P Role: RCT (Reactant), SPN (Synthetic preparation), PREP (Preparation), RACT (Reactant or reagent) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.); 87486-37-1P; 173200-35-6P; 173200-36-7P; 199296-26-9P; 308845-81-0P; 595581-85-4P; 602280-43-3P; 1178895-95-8P; 1178895-96-9P; 1178895-97-0P; 1178895-98-1P; 1178895-99-2P; 1178896-00-8P; 1178896-01-9P; 1178896-03-1P; 1178896-04-2P; 1178896-05-3P; 1178896-06-4P Role: SPN (Synthetic preparation), PREP (Preparation) (prepn. of dichloropyrazinones via Strecker reaction of primary amines, aldehydes, and trimethylsilyl cyanide, followed by cyclocondensation with oxalyl chloride under microwave irradn.)

Available from: 2009-11-24 Created: 2009-11-24 Last updated: 2018-01-12Bibliographically approved
2. Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
Open this publication in new window or tab >>Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
Show others...
2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 17, 6512-6525 p.Article in journal (Refereed) Published
Abstract [en]

Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.

Keyword
Hepatitis C virus NS3 protease, Protease inhibitors, 2(1H)-pyrazinone, Phenylglycine
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-111366 (URN)10.1016/j.bmc.2010.06.101 (DOI)000281203300032 ()20673728 (PubMedID)
Note

Uppdaterad från manuskript till Artikel 20101206

Available from: 2009-12-16 Created: 2009-12-11 Last updated: 2018-01-12Bibliographically approved
3. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
Open this publication in new window or tab >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
Show others...
2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, 1790-1801 p.Article in journal (Refereed) Published
Abstract [en]

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

National Category
Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2018-01-12Bibliographically approved
4. Design and synthesis of ribonucleotide reductase inhibitors with activity against Mycobacterium tuberculosis
Open this publication in new window or tab >>Design and synthesis of ribonucleotide reductase inhibitors with activity against Mycobacterium tuberculosis
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-172340 (URN)
Available from: 2012-04-04 Created: 2012-04-04 Last updated: 2018-01-12

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