An Efficient Approach to the Synthesis of Hydrazinyl Pseudo-Peptides by Vaezeh Fathi a ), Sorour Ramezanpour a ), Saeed Balalaie* a ) b ), Frank Rominger c ), and Hamid Reza Bijanzadeh a ) a )Peptide Chemistry Research Center, K.N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran (fax: þ 98-21-22853650; e-mail: balalaie@kntu.ac.ir) b ) Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran c ) Organisch-Chemisches Institut der Universität Heidelberg, ImNeuenheimer Feld 270, DE-69120 Heidelberg Dedicated to Prof. Fereydoun Moattar on the occasion of his 75th birthday New hydrazinyl pseudo-peptides have been obtained from Ugi four-component reaction (4CR). The 5-hydrazinyl-5-oxopentanoic acids used as starting materials were prepared by the reaction of hydrazides with anhydrides. Mild reaction conditions, high atom economy, bond-forming efficiency, and easy workup are advantages of this approach. The products have four amide bonds and high potential for H-bonding. Introduction. – Recently, pseudo-peptides have been attracting increasing attention because of their extended biological activities; in particular, they have been used in drug discovery [1 – 5] . Azapeptides are one of these modified peptides, formed through the replacement of the C a -atom of one or more amino acid residues with an N-atom ( Fig. 1). They have wide-ranging biological activities [6]. To modify peptides, suitable starting materials should be selected. The replacement of one or more a-amino acid(s) by b-amino acid(s) or other functionalized carboxylic acids is one of the known approaches to synthesize pharmaceutically active peptides [7]. Using hydrazinyl carboxylic acids and a-aminoacyl benzotriazoles by means of microwave irradiation was reported by Katritzky and co-workers for the synthesis of hydrazinyl peptides [8]. Some pseudo-peptides containing hydrazide cores have been found to exhibit HIV protease inhibitor activities [9]. In this content, Klein and Hecht reported the synthesis of some novel pseudo-peptide scaffolds based on bis(thiourea) hydrazide motif, which have the ability to inhibit b-sheet aggregation [10]. Insertion of the hydrazinyl group in the structure of peptides leads to the hydrazinyl peptides. The hydrazinyl moiety in the peptide structure induces enhanced H-bonding, which affects the peptide backbone folding. In the presence of more C¼ O and NH functional groups, this ability, as well as their biological activities can be improved [11 – Helvetica Chimica Acta – Vol. 97 (2014) 1630  2014 Verlag Helvetica Chimica Acta AG, Zürich Fig. 1. General partial structure of azapeptides