Squaric acid analogues in medicinal chemistry

In this review, we summarize the published data on squaric acid analogues with a special focus on their use in medicinal chemistry and as potential drugs. Squaric acid is an interesting small molecule with an almost perfectly square shape, and its analogues have a variety of biological activities that are enabled by the presence of significant H-bond donors and acceptors. Unfortunately, most of these compounds also exhibit reactive functionalities, and this deters the majority of medicinal chemists and pharmacologists from trying to use them in drug development. However, this group of compounds is experiencing a renaissance, and large numbers of them are being tested for antiprotozoal, antibacterial, antifungal, and antiviral activities. The most useful of these compounds exhibited IC₅₀ values in the nanomolar range, which makes them promising drug candidates. In addition to these activities, their interactions with living systems were intensively explored, revealing that squaric acid analogues inhibit various enzymes and often serve as receptor antagonists and that the squaric acid moiety may be used as a non-classical isosteric replacement for other functional groups such as carboxylate. In summary, this review is focused on squaric acid and its analogues and their use in medicinal chemistry and should serve as a guide for other researchers in the field to demonstrate the potential of these compounds based on previous research.