Synthesis and antiviral activity of N- and O-substituted amino acids

Abstract

As was shown in a previous publication [I], both the Nacyl and O-acyl derivatives ofthreo-DL-phenylserine possess antiviral activity in vitro and are capable, in the maximum tolerable dose, of completely inhibiting reproduction of the A2 influenza virus. The present article, which continues a series of communications devoted to the search for new antiv;ral compounds, reports on the synthesis and biological characterization of the derivatives of nonproteinogenic amino acids. The new compounds were obtained on the basis of DL-serine, threo-DLphenylserine, threo-DL-m-nitrophenylserine, 2-methoxy-5nitro-DL-phenylalanine, 4-methoxy-3-nitro-DL-phenylalanine, and e-aminocaproic acid. The structures of these acids and their alkyl esters were modified by introducing alkylcarboxylic and arylsulfonic acid residues and fluorenylidene radicals. The N-acyl derivatives (I-III) of threo-DL-m-nitrophenylserine ethyl ester were obtained by condensation of myristic, palmitic, and stearic acid chlorides with threo-DLm-nitrophenylserine ethyl ester hydrochloride [2] in chloroform in the presence of triethylamine. Condensation of lauryl chloride with DL-serine, phenylacetyl chloride with threoDL-phenylserine, and phenylacetyl chloride with threo-DLphenylserine ethyl ester hydrochloride [3] in an anhydrous trifluoroacetic acid medium was used to obtain O-lauroylDL-serine hydrochloride (IV. HCI), O-phenylacetyl-threoDL-phenylserine hydrochloride (V - HCI), and O-phenylacetyl-threo-DL-phenylserine (V. HCI) ethyl ester (VI. HCI), respectively. Upon crystallization of IV �9 HCI from an ethanol - water medium, and V - HCI from a methanol - water medium, these hydrochlorides lose HCI and convert into compounds IV and V, respectively. N-Propionyl-4-methoxy-" 3-nitro-DL-phenylalanine octyl ester (VII) was synthesized by condensation of 4-methoxy-3-nitro-DL-phenylalanine octyl toluenesulfonate [4] with propionyl chloride in chloroform in the presence of triethylamine. Compounds VIII and IX were obtained as described previously [5]. N-Arylsulfonyl derivatives of threo-DL-phenylserine ethyl, octyl, and