Medicinal chemistry applications

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

Oxazolines represent another very interesting scaffold for medicinal chemistry applications, since several molecules possessing this substructure show interesting biological activities [79-81]. As a result, considerable attention has been dedicated to the synthesis of these heterocycles. 

Tron GC, PiraU T, BiUington RA, Canonico PL, Sorba G, Genazzani AA (2008) Click chemistry reactions in medicinal chemistry applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med Res Rev 28(2) 278-308. doi 10.1002/med.20107... 

Chan, R, Lewis, D., Kelly, M., Ng, E.S.M., and Schriemer, D.C (2007) Frontal Affinity Chromatography Mass Spectrometry for Ligand Discovery and Characterization, in Mass Spectrometry in Medicinal Chemistry Applications in Drug Discovery (eds K. T. Wanner and G. Hofher), Wiley-VCH Verlag GmbH ... 

Thereafter, a full paper describing aminocarbonylations in water was published [29]. In addition to presenting the results achieved with aryl bromides, aminocarbo-nylation protocols for aryl iodides and aryl chlorides were also disclosed. More than 90 successful aminocarbonylations in water were presented (Scheme 4.14), including a medicinal chemistry application where this amidation procedure was used to synthesize a potent HIV-1 protease inhibitor from the aryl bromide (Scheme 4.15) [29]. 

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