Chapter 1
Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals

Clemens Lamberth and Jürgen Dinges

1.1 Introduction

Explaining the importance of carboxylic acid and its related derivatives in medicine and crop protection is best achieved by examining the number of endogenous processes and molecules that rely on the chemical nature of this functional group. From amino acid conjugation via peptide synthesis to proteins and posttranslational protein acylation to triglycerides, bile acids, and prostanoids, it is evident that carboxylic acid, ester, and amide functions contribute to the physiology of many living systems [1]. Not surprisingly then, there exists an extensive number of active ingredients bearing such functions. Roughly 25% of all commercialized pharmaceuticals contain a CO2H group [2]; a similar portion (25%) is reported to bear an amide [3]. A similar ratio is true for agrochemicals; at least 40% of all marketed crop protection agents bear a carboxylic function [4]. Several sets of criteria for the definition of the preferred chemical composition leading to optimal bioavailability for active ingredients, such as Lipinski's "Rule of Five" for oral drugs [5], Astex's "Rule of Three" for fragment-based lead discovery [6], and Brigg's "Rule of Three" for agrochemicals [7], contain the need for the presence of hydrogen-bond donors and hydrogen-bond acceptors for ideal drugs, a requirement that several carboxylic functions fulfill. This book chapter tries to highlight the most important roles that carboxylic functions play in pharmaceuticals and agrochemicals.

1.2 Solubilizer

The introduction of carboxylic acid into a biologically active compound positively impacts the water solubility of the compound. Acids are generally highly ionized at physiological pH values and therefore solvated to a greater degree and display more favorable aqueous solubilities than neutral molecules of similar lipophilicity do. In addition, the counterion influences solubility and physicochemical properties of active ingredients bearing a carboxylate [8]. The presence of charges plays a significant role in modulating solubility, lipophilicity, and thus cell permeation. However, acidic compounds are also often associated with poor permeability because they are mainly present in the deprotonated state in this pH range and cannot readily cross negatively charged lipid membranes [2]. Such solubilizing effects are even more pronounced in the presence of two or more ionized groups, especially zwitterions. For example, because of the pH gradient unique to the gastrointestinal tract, it is the piperazine moiety in the quinolone antibiotic ciprofloxacin that governs the charge state within the acidic upper gastrointestinal tract (gastric region). The elevation of the pH value in the subsequent proximal intestine results in the zwitterionic state 2 (Figure 1.1) [1, 9]. In crop protection, carboxylic acids are known for their pronounced phloem mobility, which includes the basipetal movement of an active ingredient from the leaves to the roots within a plant.

Figure 1.1 Ionization state of ciprofloxacin in the gastrointestinal tract [1].

Further proof for the effect of carboxylic acid functions on the solubility of pharmaceuticals is found in the history of antihistaminic drugs [10]. Several first-generation derivatives, such as hydroxyzine (3), were rather lipophilic compounds, which were able to cross the blood-brain barrier and had a sedating effect because they were no substrates for P-glycoproteins (P-gps). Owing to the replacement of the hydroxyl function by a carboxylic acid, cetirizine (4), a second-generation antihistaminic, is less lipophilic and therefore a P-gp substrate that limits the CNS exposure (Figure 1.2) [11, 12].

Figure 1.2 Increasing solubility of antihistaminic compounds by carboxylic acids.

1.3 Pharmacophore

A pharmacophore is the group of atoms and, therefore, also the ensemble of steric and electronic features of an active ingredient ensuring optimum molecular interactions with an enzyme and responsible for triggering or blocking its biological response [13]. The acidity of carboxylic acids, combined with the ability of all carboxylic acid derivatives to establish relatively strong electrostatic interactions and single or bifurcated hydrogen-bond bridges with the protein target, conferring both binding affinity and specificity to the drug-target interaction, is the reason that carboxylic acid functions are often the key determinant of pharmacophores [2]. Figure 1.3 shows only four examples of many pharmaceuticals and agrochemicals that rely on the presence of a carboxylic function in their pharmacophore. The terminal carboxylate of atorvastatin (5), a blood cholesterol-reducing blockbuster drug, forms a salt bridge with Lysine735 of its target enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase [14]. The carbonyl oxygen atom of the carboxylic acid function in the nonsteroidal anti-inflammatory acid flurbiprofen (6) builds a hydrogen-bond bridge with the phenol group of Tyrosine355 of cyclooxygenase-1 [15]. The broad-spectrum activity of azoxystrobin (7), the world's biggest selling fungicide, is due to the interaction of the carbonyl oxygen atom of its ester function with an amine proton of Glutamine272 in cytochrome bc1, the complex III of the respiratory chain in the mitochondria of the fungi [16]. The carbonyl oxygen of the amide function of carpropamid (8), a melanin biosynthesis-inhibiting rice fungicide, accepts a hydrogen bond from a water molecule coordinated to Tyrosine30 of scytalone dehydratase [17].

Figure 1.3 Examples for pharmacophores of active ingredients based on carboxylic acids, esters, and amides.

1.4 Prodrug

A carboxylic acid group, being usually ionized in the physiological pH range, adds to the hydrophilicity and polarity of the active ingredient. As a result, a large number of biologically active carboxylic acids display unfavorable pharmacokinetic properties such as low bioavailability because of limited uptake. Thus, the improvement of pharmacokinetic properties can be achieved by transferring the drug into a prodrug. A prodrug is a compound that itself is not biologically active, but is converted by enzymes, heat, moisture, or UV light into an intrinsically active derivative. Because of the ubiquitous availability of esterases and peptidases in many species, including human, the in vivo hydrolysis of esters and related carboxylic functions to the corresponding acids is one of the classical prodrug cases [18-23]. Such ester derivatives are called carrier prodrugs, because they often facilitate the adsorption and distribution of pharmaceuticals or agrochemicals to the desired location, followed by release of the active principle by cleavage of the carrier group through a hydrolytic reaction [19]. The ethyl ester in oseltamivir (9) increases the oral bioavailability in humans from less than 5% for the carboxylic acid parent 10 to 80% and, therefore, allows this anti-influenza antiviral agent to be administered orally [18, 20, 21]. Ester prodrugs that release a biologically active alcohol species instead of a carboxylic acid-containing drug are known to a lower content. The reason for this may be that the improvement of pharmacokinetic features is generally greater when masking the highly polar carboxylate rather than the less polar hydroxyl group [22]. An important example is the antiherpes virus agent famciclovir (11), which delivers in vivo penciclovir (12) by enzymatic ester cleavage and purine oxidation. The oral bioavailability of 4% for penciclovir is increased to 75% for famciclovir [20]. A special case of ester prodrugs are lactones, which are formed by intramolecular cyclization of hydroxyl acids and which liberate this function after cleavage. An example is the reversible ring opening of the lactone in 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin 13 to its ß-hydroxy acid open form 14 [21, 22]. The carbothioic acid S-methyl ester in the plant activator acibenzolar-S-methyl (15) [24] and the carbonate function in the insecticide spirotetramat (17) [25] are further examples of carboxylic acid derivatives, which can be employed as carrier prodrugs, and also carbamates have been used in this context (Scheme 1.1) [18, 19].

Scheme 1.1 Some examples of ester, carbonate, and carbothioic S-ester prodrugs.

Another kind of prodrugs are bioprecursors, which deliver the biologically active compound via an in vivo transformation without the need to cleave a carrier moiety. Also here, the formation of carboxylic acids seems to play an important role. The angiotensin II receptor antagonist losartan (19), which is used in antihypertensive medication, can be seen as bioprecursor prodrug, because its primary alcohol is oxidized in vivo by the cytochrome P450 enzyme CYP2C9 to the carboxylic acid 20, which represents the active principle [18, 19, 21]. In addition, the antithrombotic drug clopidogrel (21) is metabolized by cytochrome P450 enzymes to its active form 22 containing a carboxylic acid (Scheme 1.2) [18, 19].

Scheme 1.2 Losartan (19) and clopidogrel (21) as bioprecursors of carboxylic acid...