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Ultrasound-assisted improvement of drug solubility: a simple and useful method for the formation of salts from 4-hydroxy-6-methyl-3-nitropyridin-2(1H)-one

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Abstract

The low aqueous solubility of drug-like compounds has been described as one of the main problems causing the failure of new chemical entities in medicinal chemistry programmes. This paper describes our efforts to overcome lack of solubility and to produce a novel template protocol for forming salts of poorly soluble compounds. We prepared a series of 4-hydroxy-6-methyl-3-nitropyridin-2(1H)-one amine salts by using ultrasound irradiation. The poorly water-soluble molecule 4-hydroxy-6-methyl-3-nitropyridin-2(1H)-one was recently described as an inhibitor of the Mycobacterium tuberculosis orotate phosphoribosyltransferase enzyme. Salts of this molecule were prepared in 88–98 % yield from a mixture of 4-hydroxy-6-methyl-3-nitropyridin-2(1H)-one with primary and secondary amines (dimethylamine, diethylamine, dipropylamine, ethanolamine, 2-amino-2-methyl-1,3-propanediol, d-threoninol, pyrrolidine and piperidine) after ultrasound irradiation. The main advantages of this method are a significant reduction in reaction times and the use of a renewable solvent as a reaction medium. Thus the compounds are obtained after irradiation for 8 min in ethanol.

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Acknowledgments

This work was supported by funds from the National Institute of Science and Technology on Tuberculosis (INCT-TB), Decit/SCTIE/MS-MCT-CNPq-FNDCT-CAPES (Brazil) to D. S. Santos and L. A. Basso. L. A. Basso and D. S. Santos also acknowledge financial support awarded by FAPERGS-CNPq-PRONEX-2009. L. A. Basso (CNPq, 520182/99-5) and D. S. Santos (CNPq, 304051/1975-06) are Research Career Awardees of the National Research Council of Brazil (CNPq). The authors are grateful to G. O. Petersen for his help in water solubility and particle size experiments. The postdoctoral fellowship from CAPES (P. Machado) and scientific initiation fellowship from CNPq (E. Ritter) are also acknowledged.

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Authors and Affiliations

  1. Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil

    Pablo Machado, Eduarda Ritter, Anderson J. B. dos Santos, Christiano Ev Neves, Luiz A. Basso & Diógenes S. Santos

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  1. Pablo Machado
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  2. Eduarda Ritter
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  3. Anderson J. B. dos Santos
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  4. Christiano Ev Neves
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  5. Luiz A. Basso
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  6. Diógenes S. Santos
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Correspondence to Pablo Machado or Diógenes S. Santos.

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Machado, P., Ritter, E., dos Santos, A.J.B. et al. Ultrasound-assisted improvement of drug solubility: a simple and useful method for the formation of salts from 4-hydroxy-6-methyl-3-nitropyridin-2(1H)-one. Monatsh Chem 144, 1165–1170 (2013). https://doi.org/10.1007/s00706-013-0948-0

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