Fluorination is commonly employed to optimize bioactivity and pharmaco-kinetic properties of drug candidates. Aliphatic fluorination often reduces the lipophilicity (log P), but polyfluoroalkylation typically increases lipophilicity. Hence, identification of polyfluorinated motifs that nonetheless lead to similar or even reduced lipophilicities is of interest to expand the arsenal of medicinal chemistry tools in tackling properties such as compound metabolic stability or off-target selectivity. We show that changing a CF 3 -group of a perfluoroalkyl chain to a methyl group leads to a drastic reduction in lipophilicity. We also show that changing a C−F bond of a trifluoromethyl group, including when incorporated as part of a perfluoroalkyl group, to a C−Me group, leads to a reduction in log P, despite the resulting chain elongation. The observed lipophilicity trends were identified in fluorinated alkanol models and reproduced when incorporated in analogues of a drug candidate, and the metabolic stability of these motifs was demonstrated.

No abstract

The three-component reaction between a resorcinol, 1,3-dimethoxybenzene, and an alkyl aldehyde (R = C1–C11) along with BF3·OEt2 affords a C 2v-symmetric resorcin[4]­arene tetraether in one step; in most cases, the single isomer can be precipitated from the reaction mixture in moderate to excellent yields (up to 89%). The reaction is tolerant of 2-substituted resorcinols (R′ = OH, Cl, Br, Me), allowing a third type of functionality to be regioselectively incorporated during the macrocyclization.

An undergraduate laboratory was developed as part of the Drugs for Neglected Diseases initiative's Open Synthesis Network. This activity aimed to develop new compounds efficacious against visceral leishmaniasis. Students successfully synthesized, purified, and characterized ten different benzoxazole amides that were sent for biological testing against several protozoan parasites. Although all the benzoxazole amides had poor activity against L. donovani, several (2, 4, and 9) showed moderate activity against T. cruzi, T. b. rhodesiense, and T. b. brucei paired with low cell cytotoxicity. This drug discovery laboratory activity made a measurable contribution to neglected tropical disease research and was an engaging and research-orientated experience for undergraduate students. Implementation of drug discovery laboratories across a range of student levels and backgrounds is highly achievable using existing laboratory equipment and a short investment in activity preparation and can be a sustainable course component.