Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors

Raimon Puig-De-La-Bellacasa; Laura Giménez; Sofia Pettersson; Rosalia Pascual; Encarna Gonzalo; José A. Esté; Bonaventura Clotet; José I. Borrell; Jordi Teixidó

doi:10.1016/j.ejmech.2012.04.038

Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors

Raimon Puig-De-La-Bellacasa, Laura Giménez, Sofia Pettersson, Rosalia Pascual, Encarna Gonzalo, José A. Esté, Bonaventura Clotet, José I. Borrell, Jordi Teixidó

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New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC₅₀ = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC₅₀ = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC₅₀ = 1.01 μg/mL; 3.27 μM, SI >25).

Idioma original	Anglès
Pàgines (de-a)	159-174
Nombre de pàgines	16
Revista	European Journal of Medicinal Chemistry
Volum	54
DOIs	https://doi.org/10.1016/j.ejmech.2012.04.038
Estat de la publicació	Publicada - d’ag. 2012

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Puig-De-La-Bellacasa, R., Giménez, L., Pettersson, S., Pascual, R., Gonzalo, E., Esté, J. A., Clotet, B., Borrell, J. I., & Teixidó, J. (2012). Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors. European Journal of Medicinal Chemistry, 54, 159-174. https://doi.org/10.1016/j.ejmech.2012.04.038

@article{0fa1e58e765e45eda379609433c374df,

title = "Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors",

abstract = "New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC50 = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC50 = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC50 = 1.01 μg/mL; 3.27 μM, SI >25).",

keywords = "Antiviral activity, Combinatorial design, Diversity selection HIV-1, NNRTIs HEPT",

author = "Raimon Puig-De-La-Bellacasa and Laura Gim{\'e}nez and Sofia Pettersson and Rosalia Pascual and Encarna Gonzalo and Est{\'e}, {Jos{\'e} A.} and Bonaventura Clotet and Borrell, {Jos{\'e} I.} and Jordi Teixid{\'o}",

note = "Funding Information: This work was supported in part by the Fundaci{\'o} Marat{\'o} de TV3 project 020930 and Spanish Ministerio de Ciencia e Innovaci{\'o}n project SAF2010-C21617-C02 (J.I.B. and B.C.). R. Puig de la Bellacasa holds an FI scholarship from Generalitat de Catalunya and S. Pettersson from IQS. ",

year = "2012",

month = aug,

doi = "10.1016/j.ejmech.2012.04.038",

language = "English",

volume = "54",

pages = "159--174",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

Puig-De-La-Bellacasa, R, Giménez, L, Pettersson, S, Pascual, R, Gonzalo, E, Esté, JA, Clotet, B, Borrell, JI & Teixidó, J 2012, 'Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors', European Journal of Medicinal Chemistry, vol. 54, pàg. 159-174. https://doi.org/10.1016/j.ejmech.2012.04.038

Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors. / Puig-De-La-Bellacasa, Raimon; Giménez, Laura; Pettersson, Sofia et al.
In: European Journal of Medicinal Chemistry, Vol. 54, 08.2012, pàg. 159-174.

Producció científica: Article en revista indexada › Article › Avaluat per experts

TY - JOUR

T1 - Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors

AU - Puig-De-La-Bellacasa, Raimon

AU - Giménez, Laura

AU - Pettersson, Sofia

AU - Pascual, Rosalia

AU - Gonzalo, Encarna

AU - Esté, José A.

AU - Clotet, Bonaventura

AU - Borrell, José I.

AU - Teixidó, Jordi

N1 - Funding Information: This work was supported in part by the Fundació Marató de TV3 project 020930 and Spanish Ministerio de Ciencia e Innovación project SAF2010-C21617-C02 (J.I.B. and B.C.). R. Puig de la Bellacasa holds an FI scholarship from Generalitat de Catalunya and S. Pettersson from IQS.

PY - 2012/8

Y1 - 2012/8

N2 - New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC50 = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC50 = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC50 = 1.01 μg/mL; 3.27 μM, SI >25).

AB - New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC50 = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC50 = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC50 = 1.01 μg/mL; 3.27 μM, SI >25).

KW - Antiviral activity

KW - Combinatorial design

KW - Diversity selection HIV-1

KW - NNRTIs HEPT

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U2 - 10.1016/j.ejmech.2012.04.038

DO - 10.1016/j.ejmech.2012.04.038

M3 - Article

C2 - 22652226

AN - SCOPUS:84864398460

SN - 0223-5234

VL - 54

SP - 159

EP - 174

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors

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