Gas-phase acidity of sulfonamides: implications for reactivity and prodrug design J. R. B. Gomes * and P. Gomes Centro de Investigac ¸a ˜o em Quı ´mica, Departamento de Quı ´mica, Faculdade de Cie ˆncias da Universidade do Porto, Rua do Campo Alegre 687, P-4169-007 Porto, Portugal Received 25 October 2004; revised 7 January 2005; accepted 12 January 2005 Abstract—A computational study at the density functional theory level was performed on bioactive and model sulfonamides with the aim of determining the factors affecting the acidity of the sulfonamido group. The effects of introducing different substituents at either the para-aryl or the N 1 -sulfonamide positions were independently analyzed. A linear correlation was found between sulfonamide acidity and the Hammett constants or charge of the SO 2 group of substituents at the para-aryl position. Most N 1 -substituents were taken from bacteriostatic sulfonamide structures and presented a more complex behavior, possibly due to a conjugation of steric and electronic factors. In the latter situation, sulfonamide acidity and the charge of the SO 2 group were not linearly correlated. Interestingly, the acidity of the sulfonamido group was found to be correlated with the reactivity of sulfa drugs towards acylating agents. The implications for the design of suitable sulfonamide prodrugs are discussed. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction The characterization of sulfonamides as chemotherapics is more than half a century old. 1 Since then, the sulfonamido group—SO 2 NH—has been found as a key structural motif shared by a large number of bioactive compounds, spanning a wide variety of biological effects, such as antimicrobial activity, specific enzyme inhibition, hormone regulation, among others. 2 The most popular sulfonamides are p-aminobenzensulfonamides, or sulfanilamides (1), which are bacteriostatic due to their resemblance to p-aminoben- zoic acid (PABA, 2), used by bacteria in the biosynthesis of the folic acid required for their growth. 3 Most bacteriostatic sulfonamides are characterized by a p-aminoaryl moiety and structural diversity has been obtained basically by variation of the R-group linked to the N 1 atom of the sulfonamido group. Generally, this R group is a heterocyclic structure that renders the compound several times more active than the original sulfanilamide (RZ–H). In the early days of sulfonamide therapy, experimental studies by Bell et al. 4 Kumler et al. 5,6 and, 20 years later, Seydel, 7 have been devoted to the analysis of stereoelectronic factors that could be related to bacterio- static activity, paying special attention to the role of the acidity of the sulfonamido group. 4,7 These studies suggested that bacteriostatic activity is favored by decreased sulfona- mide acidity (larger DG8 values), which was confirmed in a very recent theoretical work published by Soriano-Correa and co-workers. 8 Also, distinct therapeutical effects are often associated to different acidity ranges, as illustrated by the higher acidity of antiglaucoma sulfas when compared to their cancerostatic counter parts. 9 Thus, it seems that the acidity of the sulfonamido group, and factors affecting it, are key features ruling the physico-chemical properties that modulate the sulfonamide bioactivity. Due to the well-known problems of sulfonamide therapy, especially those related to growing bacterial resistance, adverse effects and low bioavailability, 10–12 we have been working on the synthesis of N 1 -acyl and N 4 -acylsulfanila- mides as potential prodrugs of antimalarial sulfonamides. These antimalarials were acylated with amino acids and dipeptides, which are interesting carriers for drug delivery in vivo. Dipeptide carriers have several advantages, since they are non-toxic, non-immunogenic and can trigger the 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.01.034 Tetrahedron 61 (2005) 2705–2712 Keywords: Acylation; Amino acid; Bioactive; Density functional theory; Gas-phase acidity; Peptide; Prodrug; Sulfonamide. * Corresponding author. Tel.: C351 226081814; fax: C351 226082959; e-mail: jrgomes@fc.up.pt