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Fluorine is characterized by high electronegativity and small atomic size, which provide this molecule with the unique property of augmenting the potency, selectivity, metabolic stability, and pharmacokinetics of drugs. Fluorine (F) substitution has been extensively explored in drug research as a means of improving biological activity and enhancing chemical or metabolic stability. Selective F substitution onto a therapeutic or diagnostic drug candidate can enhance several pharmacokinetic and physicochemical properties such as metabolic stability and membrane permeation. The increased binding ability of fluorinated drug target proteins has also been reported in some cases. An emerging line of research on F substitution has been addressed by using ¹⁸F as a radiolabel tracer atom in the extremely sensitive methodology of positron emission tomography (PET) imaging. This review aims to report on the fluorinated drugs approved by the US Food and Drug Administration (FDA) from 2016 to 2022. It cites selected examples from a variety of therapeutic and diagnostic drugs. FDA-approved drugs in this period have a variety of heterocyclic cores, including pyrrole, pyrazole, imidazole, triazole, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, triazine, purine, indole, benzimidazole, isoquinoline, and quinoline appended with either F-18 or F-19. Some fluorinated oligonucleotides were also authorized by the FDA between 2019 and 2022. Full article

The connection of a sterically constrained 3-methyl-pyrazine ring to a N-methyl-benzimidazole unit to give the unsymmetrical α,α’-diimine ligand L5 has been programmed for the design of pseudo-octahedral spin-crossover [Fe(L5)₃]²⁺ units, the transition temperature (T_1/2) of which occurs in between those reported for related facial tris-didentate iron chromophores fitted with 3-methyl-pyridine-benzimidazole in a LaFe helicate (T_1/2 ~ 50 K) and with 5-methyl-pyrazine-benzimidazole L2 ligands (T_1/2 ~350 K). A thorough crystallographic analysis of [Fe(L5)₃](ClO₄)₂ (I), [Ni(L5)₃](ClO₄)₂ (II), [Ni(L5)₃](BF₄)₂∙H₂O (III), [Zn(L5)₃](ClO₄)₂ (IV), [Ni(L5)₃](BF₄)₂∙1.75CH₃CN (V), and [Zn(L5)₃](BF₄)₂∙1.5CH₃CN (VI) shows the selective formation of pure facial [M(L5)₃]²⁺ cations in the solvated crystals of the tetrafluoroborate salts and alternative meridional isomers in the perchlorate salts. Except for a slightly larger intra-strand interannular twist between the aromatic heterocycles in L5, the metric parameters measured in [Zn(L5)₃]²⁺ are comparable to those reported for [Zn(L2)₃]²⁺, where L2 is the related unconstrained ligand. This similitude is reinforced by comparable ligand-field strengths (∆_oct) and nephelauxetic effects (as measured by the Racah parameters B and C) extracted from the electronic absorption spectra recorded for [Ni(L5)₃]²⁺ and [Ni(L2)₃]²⁺. In this context, the strictly high-spin behavior observed for [Fe(L5)₃]²⁺ within the 5–300 K range contrasts with the close to room-temperature spin-crossover behavior of [Fe(L2)₃]²⁺ (T_1/2 = 349(5) K in acetonitrile). This can be unambiguously assigned to an intraligand arm wrestling match operating in bound L5, which prevents the contraction of the coordination sphere required for accommodating low-spin Fe^II. Since the analogous 3-methyl-pyridine ring in [Fe(L3)₃]²⁺ derivatives are sometimes compatible with spin-crossover properties, the consequences of repulsive intra-strand methyl–methyl interactions are found to be amplified in [Fe(L5)₃]²⁺ because of the much lower basicity of the 3-methyl-pyrazine ring and the resulting weaker thermodynamic compensation. The decrease of the stability constants by five orders of magnitude observed in going from [M(L2)₃]²⁺ to [M(L5)₃]²⁺ (M = Ni^II and Zn^II) is diagnostic for the operation of this effect, which had been not foreseen by the authors. Full article