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Publikasjoner (10 av 14) Visa alla publikasjoner
Vidal-Albalat, A., Kindahl, T., Rajeshwari, R., Lindgren, C., Forsgren, N., Kitur, S., . . . Linusson, A. (2023). Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes. Journal of Medicinal Chemistry, 66(9), 6333-6353
Åpne denne publikasjonen i ny fane eller vindu >>Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
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2023 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, nr 9, s. 6333-6353Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-208264 (URN)10.1021/acs.jmedchem.3c00234 (DOI)000979350900001 ()37094110 (PubMedID)2-s2.0-85156231351 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2017-00664The Kempe Foundations
Tilgjengelig fra: 2023-05-24 Laget: 2023-05-24 Sist oppdatert: 2023-09-05bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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2018 (engelsk)Inngår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 23, s. 10545-10557Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-154812 (URN)10.1021/acs.jmedchem.8b01060 (DOI)000453488200014 ()30339371 (PubMedID)2-s2.0-85058504373 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636
Tilgjengelig fra: 2019-01-07 Laget: 2019-01-07 Sist oppdatert: 2023-03-23bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and Spectroscopic Properties of Fluorinated Coumarin Lysine Derivatives
2018 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, nr 8, s. 4792-4799Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2018
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-148028 (URN)10.1021/acs.joc.7b03214 (DOI)000430898500046 ()29595263 (PubMedID)2-s2.0-85045671091 (Scopus ID)
Tilgjengelig fra: 2018-05-30 Laget: 2018-05-30 Sist oppdatert: 2023-03-24bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
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2017 (engelsk)Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 134, s. 415-427Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
Acetylcholinesterase 1, Aedes aegypti, Anopheles gambiae, Insecticides, Thiourea, Vector control
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-134612 (URN)10.1016/j.ejmech.2017.03.050 (DOI)000401677500035 ()28433681 (PubMedID)2-s2.0-85017625955 (Scopus ID)
Tilgjengelig fra: 2017-05-09 Laget: 2017-05-09 Sist oppdatert: 2023-03-24bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids
2017 (engelsk)Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, nr 11, s. 2797-2800Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2017
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-137386 (URN)10.1021/acs.orglett.7b00854 (DOI)000402850900006 ()28497693 (PubMedID)2-s2.0-85020035253 (Scopus ID)
Tilgjengelig fra: 2017-07-06 Laget: 2017-07-06 Sist oppdatert: 2023-03-24bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo
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2015 (engelsk)Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, s. 191-209Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2015
Emneord
Lipoprotein lipase, LPL, Triglyceride, Structure-activity relationship, Agonist
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-111481 (URN)10.1016/j.ejmech.2015.08.058 (DOI)000363344700015 ()26355531 (PubMedID)2-s2.0-84941116388 (Scopus ID)
Tilgjengelig fra: 2015-12-08 Laget: 2015-11-13 Sist oppdatert: 2023-03-24bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis of multiring fused 2‑pyridones via a nitrene insertion reaction: fluorescent modulators of α‑synuclein amyloid formation
Vise andre…
2015 (engelsk)Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, nr 24, s. 6194-6197Artikkel i tidsskrift, Letter (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2015
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-112810 (URN)10.1021/acs.orglett.5b03190 (DOI)000366878300065 ()26650849 (PubMedID)2-s2.0-84952684742 (Scopus ID)
Tilgjengelig fra: 2015-12-15 Laget: 2015-12-15 Sist oppdatert: 2023-03-23bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Development and optimization of simple one-step methods for the synthesis of 4-amino-substituted 1,8-naphthalimides
2014 (engelsk)Inngår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 28, s. 6175-6182Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
Oxygen heterocycles, Multicomponent reactions, Nitrogen heterocycles, Synthetic methods, crowave chemistry
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-95868 (URN)10.1002/ejoc.201402684 (DOI)000342842500008 ()2-s2.0-84991362107 (Scopus ID)
Tilgjengelig fra: 2014-12-11 Laget: 2014-11-06 Sist oppdatert: 2023-03-23bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Efficient one-step synthesis of 4-amino substituted phthalimides and evaluation of their potential as fluorescent probes
2014 (engelsk)Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, nr 25, s. 4461-4470Artikkel i tidsskrift (Fagfellevurdert) 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.

HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-91165 (URN)10.1039/c4ob00342j (DOI)000337129000024 ()2-s2.0-84902105290 (Scopus ID)
Tilgjengelig fra: 2014-07-15 Laget: 2014-07-15 Sist oppdatert: 2023-03-24bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis, optical power limiting, and DFT calculations of triplet–triplet absorption of three novel Pt(II)-diacetylide chromophores
2013 (engelsk)Inngår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, nr 19, s. 2403-2408Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Oxford: Elsevier, 2013
Emneord
Platinum acetylide, Optical power limiting, Nonlinear absorption, Triplet–triplet absorption
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-67781 (URN)10.1016/j.tetlet.2013.02.105 (DOI)000317945400027 ()2-s2.0-84875961538 (Scopus ID)
Tilgjengelig fra: 2013-04-03 Laget: 2013-04-03 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-6548-6158