Fluorinated Cycloalkyl Building Blocks for Drug Discovery

Abstract

The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

Mono‐ and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties

“…It is now widely recognized that fluorinated organic compounds have become extremely popular in the discovery and development of novel drugs, with numerous success stories occurring at an increasing rate over the last decades [1–9] . Introducing fluorine atoms into the molecules of interest can drastically change their physicochemical, biological, and other properties, which has been covered in several review articles [10–12] . While the general effects of such modifications are more or less understood, the rational application of fluorinated building blocks in design of potential drugs is still needs to be achieved in full [13] …”

4,4‐Difluorospiro[2.2]pentan‐1‐yl – A Fluorinated Substituent To Expand the Synthetic and Medicinal Chemists’ Toolbox

“…The dependance of ΔLogP upon gem-difluorination on the substituent present in the cyclic system, especially for the cyclopropane derivatives, has been already outlined previously by us. [39,40] Similar (but opposite) effects were observed for aqueous solubility (S w ): while 24 was nearly twice more soluble than 22 c, 25 -nearly twice less than 22 d.…”

“…LogP and aqueous solubility (S w ) were measured for these derivatives and compared with those for monocyclic counterparts 24 c-31 d. [38,39] The obtained results are in line with the previous observations on the gem-difluorination of cycloalkane derivatives. [39,40] In particular, compounds 10 and 11 have pK a values by 0.78 and 1.97 units lower than parent spiro[2.2]pentane derivatives 22 a and 22 b, respectively, which is similar to the monocyclic compounds bearing the CF 2 unit at the γ position to the functional group (À ΔpK a = 0.7 � 0.2 and 1.4 � 0.3, respectively). The effect of the gem-difluorination on the lipophilicity is less obvious: while anilide 24 is by 0.31 LogP units more lipophilic than non-fluorinated analog 22 c, N-benzoyl derivative 25 has slightly lower LogP value as compared to 22 d (by 0.04 units).…”

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

“…Fluorination is another very common method of fine-tuning drug molecules [ 22 , 23 , 24 ]. This concerns, for instance, the development of glycomimetic drugs [ 25 ], metal complexes [ 26 ], and nucleosides [ 27 ], with all of these exerting also anticancer activity.…”