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Fluorinated compounds supply alternatives for drug discovery

In medicinal chemistry, the chemical group known as amide is king. The amides include a nitrogen atom linked to a carbonyl group (C = O) and seem in all medication, besides 4, among the many 40 most bought medication in 2018 (see go.nature. com / 30f709w). Scattolin et al.1, writing in Nature, broaden the vary of amides out there for drug discovery by exhibiting easy methods to synthesize a beforehand inaccessible group of compounds, N-trifluoromethylamides, wherein the amide is carefully related to three fluorine atoms .

Amides are prevalent in compounds essential in medication, not solely as a result of they’re significantly secure, but in addition as a result of they’re polar (they comprise areas of excessive density of optimistic and damaging electrical costs), which which permits medication containing amides to work together with organic receptors and enzymes. On this regard, using amides in medication follows the instance of nature – amide teams set up the hyperlinks between amino acid residues in proteins. However medication should not solely work together with organic targets; they have to additionally face up to speedy metabolic degradation within the advanced setting of the human physique.

One effectively established option to defend molecules in opposition to this degradation is to make use of fluorine atoms. Like amides, carbon – fluorine bonds (C – F) are polar and unreactive. However not like amides, they’re virtually fully international to biology – which signifies that metabolic enzymes have hassle degrading them shortly. This makes the incorporation of fluorine atoms an efficient option to enhance metabolic stability in addition to different fascinating properties of drug compounds2.

The mixture of amide teams with fluorine atoms could also be a very profitable technique for drug growth. Certainly, atorvastatin, a ldl cholesterol reducer, is the best-selling drug of all time. However the synthesis of molecules wherein amides and fluorine atoms are carefully related is much from easy. Makes an attempt to assemble fluorinated amides typically require response situations that may trigger degradation of delicate chemical teams within the goal molecule.

Scattolin et al. describe a sensible resolution for the synthesis of a household of fluorinated, in any other case almost inaccessible, amines containing an N-trifluoromethyl group (N-CF3; Fig. 1). The authors intelligently overcome the reluctance of fluoride ions to participate in helpful reactions through the use of a comparatively reactive salt, silver fluoride, to advertise the formation of bonds between two reagents that shall be acquainted to natural chemists however that are not often mixed. The primary of those is a sulfur-containing compound known as isothiocyanate (Determine 1) – extra particularly, the compound that promotes the basic Edman degradation response, used within the early strategies of sequence dedication. amino acid proteins. Researchers in the identical group as Scattolin et al. beforehand used3.four silver ions to advertise the alternative of sulfur atoms by fluorine. Silver fluoride has the identical position within the current work: it extracts the sulfur from the Edman reagent and replaces it with three fluorine atoms, forming an intermediate compound containing a trifluoromethyl group (CF3).

Determine 1 | The synthesis of N-trifluoromethylamide compounds. The N-trifluoromethylamides comprise a trifluoromethyl group (purple) linked to an amide group (blue) and have been virtually unimaginable to fabricate. R1 and R2 symbolize any chemical group. Scattolin et al.1 report a sensible synthesis of those compounds, that are of curiosity for drug discovery. The authors handled an isothiocyanate with silver fluoride (AgF) by producing an intermediate compound wherein a trifluoromethyl group is bonded to a nitrogen atom. This intermediate reacts with bis (trichloromethyl) carbonate (CO (OCCl3) 2) within the presence of silver fluoride to kind a carbamoyl fluoride. Remedy of this compound with magnesium-containing reagents, often called Grignard reagents (R2MgX, the place X is a halogen atom) produces N-trifluoromethylamides. Facet merchandise of the reactions usually are not proven.

The second reagent is bis (trichloromethyl) carbonate (Determine 1), which is usually used to make amides and amide derivatives. The authors report that, when utilized in mixture with silver fluoride, this carbonate traps the intermediate often containing little or no CF3-containing reagent to kind a compound known as carbamoyl fluoride. It’s this compound that constitutes the conceptual breakthrough of the work of Scattolin and his colleagues.

Carbamoyl fluoride already comprises the carbon – nitrogen bond of the goal amide, thus avoiding the standard difficulties related to the manufacture of fluorinated amides. As well as, it’s secure sufficient to be remoted, however sufficiently reactive to represent a constituent ingredient of the synthesis of a variety of N-trifluoromethylamides – which Scattolin et al. put together by reacting carbamoyl fluoride with numerous magnesium-containing compounds often called Grignard reagents (Determine 1). The authors present that chemical teams known as ureas and carbamates can be manufactured on this final step, thus increasing the applying prospects of chemistry past fluorinated amides.

On this work, Scattolin and his colleagues carried out a formidable choreography of the reactions of a number of seemingly incompatible and extremely reactive reagents, completely controlling which encounter, when and the place. The authors display that their technique can be utilized not solely to make easy N-trifluoromethylamide molecules, but in addition for chemically delicate molecules corresponding to these based mostly on amino acids, drug scaffolds, and the monomers used to make N-trifluoromethylamide molecules. the manufacture of polymer supplies.

The reported reactions will permit pharmacists to arrange beforehand unavailable compounds for testing in drug discovery applications – a few of these compounds could show new organic actions. The addition of a methyl group to the nitrogen atom of an amide in drug candidates has lengthy been used to change the conformations adopted by these molecules6, thus altering their organic actions; the power to fabricate N-trifluoromethylamides will broaden the scope of this technique.

Nonetheless, the brand new chemistry has drawbacks that must be solved earlier than it may be used on the economic scale crucial for the manufacture of a drug. The principle drawback is that the reactions require substantial quantities of the required reagents: each fluorine atom launched right into a molecule, plus two others expelled throughout the response, is accompanied by a silver atom, which signifies that 5 silver atoms are wanted for the response. every molecule of product. That is acceptable for the preliminary phases of drug discovery (growth and lead optimization), which usually contain milligrams to grams of drug candidates. Nonetheless, it could not be viable for the synthesis of compounds on the kilogram scale required for medical trials, not to mention for industrial manufacturing processes, due to the fee and the big quantity of waste produced. Additional progress shall be wanted to discover a option to synthesize N-trifluoromethylamides sustainably on such a big scale.

Along with medical chemistry, Scattolin et al. Revealed that isothiocyanate teams can act as precursors of trifluoromethyl teams bonded to nitrogen atoms. Their reactions could discover a lot wider use in chemical synthesis, the place the potential of producing trifluoromethyl-substituted nitrogen compounds could facilitate the design and synthesis of catalysts or supplies with novel properties.

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