Carboxylic acids

The carboxylic acid group is one of the most prevalent functional groups across approved drug classes, appearing in NSAIDs, statins, beta-lactam antibiotics, ACE inhibitors, and a growing number of targeted small molecules. Its dual hydrogen bond donor and acceptor character, combined with the capacity to engage in ionic interactions with basic residues such as arginine, lysine, and histidine in enzyme active sites, makes the carboxylate a potent pharmacophoric element. At physiological pH, the carboxylic acid is predominantly ionised to its carboxylate anion, which governs both binding selectivity and physicochemical properties including aqueous solubility, membrane permeability, and plasma protein binding. This ionisable character is frequently exploited in structure-activity relationship (SAR) campaigns: the pKa of the carboxylic acid influences the fraction of unionised species available for passive permeation, and bioisosteric replacement with tetrazoles, acylsulfonamides, or phosphonic acids is a common strategy to modulate these properties while retaining the key binding interactions. The carboxylic acid also serves as a metabolic endpoint in oxidative drug metabolism and as a synthetic handle for amide coupling, esterification, and carboxylate activation in pharmaceutical manufacture.

Two first-in-class FDA-approved drugs approved in 2023 illustrate the pharmacological centrality of the carboxylic acid group. Daprodustat (Jesduvroq, GlaxoSmithKline), the first HIF prolyl hydroxylase inhibitor (HIF-PHI) approved in the US, was granted FDA approval in February 2023 for the treatment of anaemia due to chronic kidney disease in adults on dialysis, the first new medicine approved for this indication in over 30 years. Its glycine-derived carboxylic acid is the key pharmacophore for bidentate chelation of the active-site iron(II) of the HIF-PHD enzymes, mimicking the 2-oxoglutarate co-substrate and competitively inhibiting the enzyme to stabilise HIF-1α and HIF-2α transcription factors that drive erythropoietin production. Iptacopan (Fabhalta, Novartis), the first oral complement factor B inhibitor, was approved in December 2023 as the first oral monotherapy for paroxysmal nocturnal haemoglobinuria (PNH). Its 4-piperidinyl benzoic acid pharmacophore is central to potent, selective binding within the factor B serine protease active site, where the carboxylate engages in a direct salt bridge with Arg751, a key residue at the S1 subsite, and this interaction drives the compound's exceptional selectivity for factor B over structurally related serine proteases.

In organic synthesis, the carboxylic acid is a substrate and product in a broad range of fundamental named reactions. The Fischer esterification, acid-catalysed condensation of a carboxylic acid with an alcohol, is one of the most widely applied esterification routes in pharmaceutical synthesis. The Curtius rearrangement converts carboxylic acids to isocyanates via acyl azide intermediates, providing access to amines, carbamates, and ureas from carboxylic acid starting materials. The Arndt-Eistert reaction homologates a carboxylic acid by one carbon via an acyl chloride, diazomethane, and Wolff rearrangement sequence, useful for generating beta-amino acid derivatives from alpha-amino acids. The Hunsdiecker reaction converts silver carboxylate salts to alkyl halides via radical decarboxylation, and the Hell-Volhard-Zelinsky reaction introduces alpha-halogen substituents adjacent to carboxylic acids, providing versatile intermediates for further functionalisation. Coupling reagents including DCC, HATU, and T3P activate carboxylic acids towards amide bond formation, the most commonly executed transformation in pharmaceutical synthesis.

Emerging synthetic techniques are rapidly expanding the utility of carboxylic acids as starting materials. In photochemistry, visible-light photoredox catalysis has established the carboxylic acid as a practical radical precursor through oxidative decarboxylation: N-hydroxyphthalimide (NHPI) esters, readily prepared from carboxylic acids, undergo single-electron reduction under photoredox conditions to generate carbon-centred radicals that participate in Giese-type additions, C-C and C-heteroatom bond formations, and late-stage diversification of complex intermediates. Direct decarboxylative C(sp2)-C(sp3) cross-coupling combining photoredox and nickel catalysis enables coupling of aliphatic carboxylic acids with aryl halides, providing retrosynthetic disconnections of high strategic value. Electrochemically, the Kolbe electrolysis, anodic oxidation of carboxylate anions to generate alkyl radicals via decarboxylation, is one of the oldest electrochemical reactions in organic chemistry and has found modern application in the decarboxylative coupling of fatty acids and complex carboxylic acid substrates under scalable conditions. Non-Kolbe variants in which the intermediate carbocation is intercepted rather than dimerised expand this further, enabling direct access to ethers, olefins, and acetates from carboxylic acid starting materials without additional oxidants.