XII Iberian Meeting of Electrochemistry XVI Meeting of the ...

XII Iberian Meeting of Electrochemistry & XVI Meeting of the Portuguese Electrochemical Society PB 11
Acid dissociation constants for several potential
anti-tubercular drugs:
isoniazid and thiobenzanilide derivatives
M. C ristina Ventura, 1,2 A. Catarina Bastos, 1 M. João Sarmento, 1 João Manso, 1
Susana Borges, 1 Vanessa Miranda, 1 Susana Santos, 1 Filomena Martins 1
1
Faculdade de Ciências de Lisboa, Departamento de Química e Bioquímica, Centro de Química e
Bioquímica (CQB), Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal
2 Instituto Superior de Educação e Ciências, Alameda das Linhas de Torres,
179, 1750 Lisboa, Portugal
mcventura@fc.ul.pt
According to the most recent WHO data [1], tuberculosis (TB) kills 1.8 million people
every year and one-third of the world's population is currently infected with the
Mycobacterium tuberculosis (M.tb) bacillus. Moreover, 9.4 million new TB cases were
reported in 2008 from which 1.4 million refer to people co-infected with HIV.
Isoniazid (INH) is one of the most powerful first-line drugs in multi-therapeutic
regimens but an increasing number of M.tb INH-resistant strains have been reported [2].
The identification of INH derivatives, or derivatives of other families, with antitubercular
activity comparable to that of INH but which retain their activity against a
panel of INH-resistant strains, would obviously be of invaluable importance [3].
In the process of screening and pre-formulation of potential new drugs, it is essential the
knowledge of several physicochemical properties, namely their acid dissociation
constants (pKa) which affect the passive transport across biological membranes and
therefore the activity in the living organism. However, many of these compounds are
scarcely soluble in water, making it necessary to determine their pKa values either in
organic solvents or in aqueous mixtures and then extrapolate to water. The rationale of
the effect of pK
can provide useful information regarding the feasibility of these compounds as drug-like
candidates.
In this work we performed solubility and stability tests by UV-Vis spectrometry, at 25.0
ºC, for several isoniazid and thiobenzanilide derivatives, some of which designed and
synthesized on the basis of QSAR studies. For each compound, pKa values were
determined by potentiometry in 4/5 methanol/water mixtures, also at 25.0 ºC. From
these values aqueous pKa values were computed by extrapolation using the Yasuda
Shedlovsky method. Bioavailability was assessed on the basis of estimated ionization
degrees at physiological pH.
Acknowledgments: This work was funded under project PTDC/QUI/67933/2006. ACB gratefully
acknowledges a BII grant from F CT/F CUL and MJS a grant from UL/Fundação Amadeu Dias,
both in 2008/2009.
References
[1] WHO Report 2009; Global Tuberculosis Control, Epidemiology, Strategy, Financing, Geneve,
2009.
[2] Suarez, J.; Ranguelova, K.; Schelvis, J.P.M.; Magliozzo, R.S. J. Biol. Chem., 2009, 284, 16146.
[3] Ventura, C.; Martins, F. J. Med. Chem., 2008, 51, 612.
September, 811, 2010. ISEL - Lisbon 77