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Publications (10 of 13) Show all publications
Knutsson, S., Engdahl, C., Kumari, R., Forsgren, N., Lindgren, C., Kindahl, T., . . . Linusson, A. (2018). Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency. Journal of Medicinal Chemistry, 61(23), 10545-10557
Open this publication in new window or tab >>Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 23, p. 10545-10557Article in journal (Refereed) Published
Abstract [en]

Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-154812 (URN)10.1021/acs.jmedchem.8b01060 (DOI)000453488200014 ()30339371 (PubMedID)
Funder
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Shukla, L., Moodie, L. W. K., Kindahl, T. & Hedberg, C. (2018). Synthesis and Spectroscopic Properties of Fluorinated Coumarin Lysine Derivatives. Journal of Organic Chemistry, 83(8), 4792-4799
Open this publication in new window or tab >>Synthesis and Spectroscopic Properties of Fluorinated Coumarin Lysine Derivatives
2018 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, no 8, p. 4792-4799Article in journal (Refereed) Published
Abstract [en]

The site-selective incorporation of fluorescent amino acids into proteins has emerged as a valuable alternative to expressible protein reporters. For successful application, a robust and scalable, yet flexible, route to non-natural amino acids is required. This work describes an improved synthesis of coumarin-conjugated lysine derivatives where fluorinated variants are accessed. These analogues can be utilized at low pH and should find application probing biological processes that operate under acidic conditions.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-148028 (URN)10.1021/acs.joc.7b03214 (DOI)000430898500046 ()29595263 (PubMedID)
Available from: 2018-05-30 Created: 2018-05-30 Last updated: 2018-06-09Bibliographically approved
Knutsson, S., Kindahl, T., Engdahl, C., Nikjoo, D., Forsgren, N., Kitur, S., . . . Linusson, A. (2017). N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes. European Journal of Medicinal Chemistry, 134, 415-427
Open this publication in new window or tab >>N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
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2017 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 134, p. 415-427Article in journal (Refereed) Published
Abstract [en]

Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.

Keywords
Acetylcholinesterase 1, Aedes aegypti, Anopheles gambiae, Insecticides, Thiourea, Vector control
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-134612 (URN)10.1016/j.ejmech.2017.03.050 (DOI)000401677500035 ()28433681 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-06-09Bibliographically approved
Moodie, L. W. K., Chammaa, S., Kindahl, T. & Hedberg, C. (2017). Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids. Organic Letters, 19(11), 2797-2800
Open this publication in new window or tab >>Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids
2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 11, p. 2797-2800Article in journal (Refereed) Published
Abstract [en]

Incorporation of the fluorogenic l-(7-hydroxycoumarin-4-yl)ethylglycine into proteins is a valuable biological tool. Coumarins are typically accessed via the Pechmann reaction, which requires acidic conditions and lacks substrate flexibility. A Pd-mediated coupling is described between o-methoxyboronic acids and a glutamic acid derived (Z)-vinyl triflate, forming latent coumarins. Global deprotection with BBr3 forms the coumarin scaffold in a single step. This mild and scalable route yielded five analogues, including a probe suitable for use at lower pH.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-137386 (URN)10.1021/acs.orglett.7b00854 (DOI)000402850900006 ()28497693 (PubMedID)
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2018-06-09Bibliographically approved
Caraballo, R., Larsson, M., Nilsson, S. K., Ericsson, M., Qian, W., Tran, N. P., . . . Elofsson, M. (2015). Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo. European Journal of Medicinal Chemistry, 103, 191-209
Open this publication in new window or tab >>Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
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2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, p. 191-209Article in journal (Refereed) Published
Abstract [en]

The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Lipoprotein lipase, LPL, Triglyceride, Structure-activity relationship, Agonist
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-111481 (URN)10.1016/j.ejmech.2015.08.058 (DOI)000363344700015 ()26355531 (PubMedID)
Available from: 2015-12-08 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Singh, P., Chorell, E., Krishnan, K. S., Kindahl, T., Ådén, J., Wittung-Stafshede, P. & Almqvist, F. (2015). Synthesis of multiring fused 2‑pyridones via a nitrene insertion reaction: fluorescent modulators of α‑synuclein amyloid formation [Letter to the editor]. Organic Letters, 17(24), 6194-6197
Open this publication in new window or tab >>Synthesis of multiring fused 2‑pyridones via a nitrene insertion reaction: fluorescent modulators of α‑synuclein amyloid formation
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2015 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 24, p. 6194-6197Article in journal, Letter (Refereed) Published
Abstract [en]

An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C−H amination reaction is reported. All the synthesized polyheterocycles were evaluated for their fluorescent properties and effect on α-synuclein amyloid formation.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-112810 (URN)10.1021/acs.orglett.5b03190 (DOI)000366878300065 ()26650849 (PubMedID)
Available from: 2015-12-15 Created: 2015-12-15 Last updated: 2018-06-07Bibliographically approved
Kindahl, T., Chorell, E. & Chorell, E. (2014). Development and optimization of simple one-step methods for the synthesis of 4-amino-substituted 1,8-naphthalimides. European Journal of Organic Chemistry (28), 6175-6182
Open this publication in new window or tab >>Development and optimization of simple one-step methods for the synthesis of 4-amino-substituted 1,8-naphthalimides
2014 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 28, p. 6175-6182Article in journal (Refereed) Published
Abstract [en]

The 1,8-naphthalimide central fragment can be found in a vast number of bioactive compounds and drugs in clinical trials, and can be recognized from their use as fluorescent probes. Of key importance for the fluorescent properties of the scaffold is the 4-amino substituent, which has also proven to be critical in several other chemical and biological applications. Because of the great interest in 1,8-naphthalimides in general, and 4-amino-substituted 1,8-naphthalimides in particular, we have developed and optimized one-step procedures with which to access these derivatives by using an experimental design approach. The multivariate studies of temperature, reaction time, and equivalents of substrates identified conditions with close to quantitative yields that could be applied to generate a range of 4-amino-substituted 1,8-naphthalimides in high yields.

Keywords
Oxygen heterocycles, Multicomponent reactions, Nitrogen heterocycles, Synthetic methods, crowave chemistry
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-95868 (URN)10.1002/ejoc.201402684 (DOI)000342842500008 ()
Available from: 2014-12-11 Created: 2014-11-06 Last updated: 2018-06-07Bibliographically approved
Kindahl, T. & Chorell, E. (2014). Efficient one-step synthesis of 4-amino substituted phthalimides and evaluation of their potential as fluorescent probes. Organic and biomolecular chemistry, 12(25), 4461-4470
Open this publication in new window or tab >>Efficient one-step synthesis of 4-amino substituted phthalimides and evaluation of their potential as fluorescent probes
2014 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, no 25, p. 4461-4470Article in journal (Refereed) Published
Abstract [en]

The phthalimide scaffold is recognized from bioactive compounds and marketed drugs, but can also be used as fluorescent probes by introducing a 4-amino substituent. Unfortunately, a general and convenient method to synthesize various 4-amino substituted phthalimides has been lacking. To overcome this, an atom efficient one-step synthesis of 4-amino substituted phthalimides in good to excellent yields that tolerate a wide range of substituents has been developed. Several of the generated compounds display interesting solvatochromic properties with high quantum yield of fluorescence in non-polar solvents that are significantly reduced in polar protic solvents. Many of these compounds displayed non-toxic properties and non-detectable unspecific binding and can thus potentially be linked to a substrate and used as fluorescent probes. Furthermore, bioactive and fluorescent 4-amino substituted phthalimides with IC50-values in the low micromolar range in cell-based assays have been identified and could be used to study uptake and distribution. The developed convenient synthetic method is thus valuable not only to construct fluorescent probes and fluorescent bioactive compounds to gain information about target binding, but also from a structure activity point of view in the various areas where the phthalimides have displayed activity.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-91165 (URN)10.1039/c4ob00342j (DOI)000337129000024 ()
Available from: 2014-07-15 Created: 2014-07-15 Last updated: 2018-06-07Bibliographically approved
Kindahl, T., Öhgren, J., Lopes, C. & Eliasson, B. (2013). Synthesis, optical power limiting, and DFT calculations of triplet–triplet absorption of three novel Pt(II)-diacetylide chromophores. Tetrahedron Letters, 54(19), 2403-2408
Open this publication in new window or tab >>Synthesis, optical power limiting, and DFT calculations of triplet–triplet absorption of three novel Pt(II)-diacetylide chromophores
2013 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, no 19, p. 2403-2408Article in journal (Refereed) Published
Abstract [en]

Three novel rod-like Pt(II)-diacetylides have been synthesized. When subjected to intense laser light, all three compounds showed strong optical power limiting at 532 and 600 nm. DFT calculated triplet–triplet electronic excitations were found to correlate with the nonlinear absorption.

Place, publisher, year, edition, pages
Oxford: Elsevier, 2013
Keywords
Platinum acetylide, Optical power limiting, Nonlinear absorption, Triplet–triplet absorption
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-67781 (URN)10.1016/j.tetlet.2013.02.105 (DOI)000317945400027 ()
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2018-06-08Bibliographically approved
Kindahl, T., Ellingsen, P. G., Lopes, C., Brannlund, C., Lindgren, M. & Eliasson, B. (2012). Photophysical and DFT Characterization of Novel Pt(II)-Coupled 2,5-Diaryloxazoles for Nonlinear Optical Absorption. Journal of Physical Chemistry A, 116(47), 11519-11530
Open this publication in new window or tab >>Photophysical and DFT Characterization of Novel Pt(II)-Coupled 2,5-Diaryloxazoles for Nonlinear Optical Absorption
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2012 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 116, no 47, p. 11519-11530Article in journal (Refereed) Published
Abstract [en]

Several new bis-phosphine platinum(II) complexes with 2,5-diaryl-substituted oxazole-containing alkyne ligands have been synthesized and optically characterized in solution. Measurements of nonlinear absorption showed strong attenuation of laser light at 532 and 600 nm. The light absorption of the Pt complexes was shifted from the near-UV region for the ground state to the red region for the excited triplet state, and was associated with large extinction coefficients. The optical limiting effect can be explained by triplet-triplet excited state absorption in conjunction with fast excited singlet to-triplet intersystem crossing and slow triplet to-ground-state decay, in comparison with the pulse length of the laser. DFT calculations show good predictability of the S-0-S-1 and S-0-T-1 energy gaps and offer insight into the interaction strength between Pt and the alkyne ligands. The use of this type of ligand, with weak absorption for the Pt(II) complexes in the visual wavelength range as a key feature, enables the possibility to further improve these molecular systems for nonlinear absorption applications.

National Category
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-63024 (URN)10.1021/jp307312v (DOI)000311650200005 ()
Available from: 2012-12-28 Created: 2012-12-27 Last updated: 2018-06-08Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6548-6158

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