Organic Carbamates in Drug Design!

Carbamate-bearing molecules play an important role in modern drug discovery and medicinal chemistry. Organic carbamates (or urethanes) are structural elements of many approved therapeutic agents. Structurally, the carbamate functionality is related to amide-ester hybrid features and, in general, displays very good chemical and proteolytic stabilities. Carbamates are widely utilized as a peptide bond surrogate in medicinal chemistry. This is mainly due to their chemical stability and capability to permeate cell membranes. Another unique feature of carbamates is their ability to modulate inter- and intramolecular interactions with the target enzymes or receptors. The carbamate functionality imposes a degree of conformational restriction due to the delocalization of nonbonded electrons on nitrogen into the carboxyl moiety. In addition, the carbamate functionality participates in hydrogen bonding through the carboxyl group and the backbone NH. Therefore, substitution on the O- and N-termini of a carbamate offers opportunities for modulation of biological properties and improvement in stability and pharmacokinetic properties. Carbamates have been manipulated for use in the design of prodrugs as a means of achieving first-pass and systemic hydrolytic stability. Carbamate derivatives are widely represented in agricultural chemicals, such as pesticides, fungicides, and herbicides. They play a major role in the chemical and paint industry as starting materials, intermediates, and solvents. Furthermore, organic carbamates serve a very important role as optimum protecting groups for amines and amino acids in organic synthesis and peptide chemistry.

Peptide-based molecules are an important starting point for drug discovery, especially in the design of enzyme inhibitors. Because of their high affinity and specificity toward biological functions, peptide-based molecules also serve as valuable research tools. However, the poor in vivo stability, inadequate pharmacokinetic properties, and low bioavailability have generally limited their broader utility. Hence, a variety of peptide mimics are being developed to improve drug-like character along with increased potency, target specificity, and longer duration of action. To this end, several classes of peptidomimetics are tailored by replacing the native amide bond with unnatural linkages such as retro-amide, urea, carbamate, and heterocycles as peptide bond surrogates. These functionalities confer metabolic stability toward aminopeptidases, the enzymes involved in the metabolism of peptide-like drugs. The carbamate’s emerging role in medicinal chemistry is also due to its chemical stability and to its capability to increase permeability across cellular membranes. These attributes of organic carbamates have been exploited in drug design. As a result, the carbamate motif is becoming the choice for peptide bond surrogates.

Over the years, a variety of carabamates have been prepared by utilizing the Hofmann rearrangement of amides, the Curtius rearrangement of acyl azides,the reductive carbonylation of nitroaromatics, the carbonylation of amines, the reaction of alcohols with isocyanates, and carbon dioxide alkylation.The Hofmann rearrangement is well-recognized as a useful method to convert primary carboxamides to amines or carbamates, characterized by the reduction of one carbon in the structure.Much effort has been devoted to the development of modified reagents to optimize the Hofmann rearrangement since the classical method for this transformation, involving the use of an alkaline solution of bromine, is unsatisfactory and unreliable. A variety of oxidants and bases have been proposed as modified agents, e.g., iodine(III) reagents such as PhI(OAc)2, MeOBr, NBS-CH3ONa, NBS-KOH, lead tetraacetate, and benzyltrimethylammonium tribromide. These modified methods, however, require more than 1 equiv or an excess amount of the oxidizing reagent, which is not very convenient.The Curtius rearrangement is the thermal decomposition of acyl azides into the isocyanate intermediate. This method is widely employed in the transformation of carboxylic acids into carbamates and ureas. Acyl azides are usually prepared from carboxylic acid derivatives such as acyl chlorides, mixed anhydrides, and hydrazides. Subsequent isocyanate intermediates can be trapped by a variety of nucleophiles to provide the carbamate derivatives. The acid chloride method is not suitable for acid-sensitive functionalities. One-pot transformations of carboxylic acids into carbamates avoids the isolation of unstable acyl azides. However, protocols involving the use of diphenylphosphoryl azide (DPPA) for the one-pot Curtius reaction are also characterized by issues related to toxicity and the high boiling point of DPPA, which creates difficulties during workup and purification. Other general methods for carbamate preparation involve the use of the highly toxic phosgene,61 phosgene derivatives, or isocyanates. (J Med Chem. 2015 Apr 9; 58(7): 2895–2940.)

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