Current Pharmaceutical Design, 2008, 14, 1001-1047 1001 1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Recent Developments in the Chemistry and in the Biological Applications of Amidoximes K.C. Fylaktakidou 1, * , D.J. Hadjipavlou-Litina 2, * , K.E. Litinas 3 , E.A. Varella 3 and D.N. Nicolaides 3 1 Molecular Biology and Genetics Department, Democritus University of Thrace, Alexandroupolis 68100, Greece; 2 Department of Pharmaceutical Chemistry, School of Pharmacy and 3 Laboratory of Organic Chemistry, Department of Chemistry, Aristotle Univer- sity of Thessaloniki, Thessaloniki 54124, Greece Abstract: Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antivi- ral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/ antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoxi- mes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also exten- sively reviewed. Key Words: Amidoximes, amidines, prodrugs, NO donors, biological activities. . INTRODUCTION Amidoximes are compounds bearing both a hydroxyimino and an amino function at the same carbon atom, and thus closely asso- ciated with amides, amidines and hydroxamic acids. An extensive review about the synthesis and chemistry of amidoximes, as well as few aspects concerning biological and technical applications, ap- peared in 1992 by Nicolaides and Varella, covering fully the litera- ture up to the end of 1990 [1]. Amidoximes are versatile building blocks for the synthesis of various heterocycles [2-4]. In analytical chemistry, amidoximes are used as selective extracting reagents for quantitative spectropho- tometric determination of toxic metal cations such as cadmium (II), vanadium (V), and osmium (VIII) [5,6]. As a metal ion chelating functional group, the amidoxime moiety represents a promising pharmacophore for the development of metalloenzyme inhibitors [2,7]. The discovery of their transformation by various enzymes to amides with a subsequent release of NO or their reduction to amidi- nes attracted the scientists to use this group as a potent pharma- cophore, in the design of more efficient drugs/prodrugs. Concerning the chemistry of amidoximes, during the last 15 years some new methodologies as well as improvements of previ- ously reported reactions appeared in the literature. Their extensive description is out of the scope of this review, however we wish to highlight into some general methods of syntheses or reactions in- volving amidoximes, acylated amidoximes, and amidines, which are the main subject of the present review. This issue, as well as the numerous examples of amidoximes possessing very important bio- logical activities such as: antituberculotic, antibacterial, bacte- riostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anx- iolytic-antidepressant, anti-inflammatory/antioxidant, antiaggrega- tory (NO donors), plant growth regulation, has prompted us to pay *Address correspondence to these authors at the Molecular Biology and Genetics Department, Democritus University of Thrace, Alexandroupolis 68100, Greece; E-mail: kfylakta@mbg.duth.gr and Department of Pharma- ceutical Chemistry, School of Pharmacy, Aristotle University of Thessalo- niki, Thessaloniki, 54124, Greece; E-mail: hadjipav@pharm.auth.gr attention on this interesting class of compounds and deal with as- pects concerning chemical and biological questions on them. . THE CHEMISTRY OF AMIDOXIMES .1. Methods for the Synthesis of Amidoximes and Simple De- rivatives According to the references sited at 90’s review [1], amidoxi- mes can be synthesized upon a reaction of a proper nitrile and hy- droxylamine (Scheme 1). This reaction is not only very efficient but useful as well, since nitriles are compounds readily available, and the obtained yields of the amidoximes are usually high. Expanding of the utility of this conventional method, is the fact that amidoxi- mes, nowadays, can be attached on a solid support. Therefore the reaction can proceed by treating resin-bound nitriles with hydroxy- lamine [8,9], and the resulting resin bounded amidoximes can be further used in a variety of combinatorial techniques and applica- tions. Scheme 1. Synthesis of amidoximes via nitriles. Reactions depicted in Scheme 1, lead to N-unsubstituted ami- doximes. An approach [1] to both unsubstituted and substituted compounds involves the interaction of ammonia and amines respec- tively, on hydroxamoyl chlorides via and on nitriloxides, according to Scheme 2. Scheme 2. Synthesis of substituted amidoximes via nitriloxides. RCN + NH 2 OH R NOH NH 2 I II R NOH Cl base R C N + O - R 1 R 2 NH R NOH NR 1 R 2 III IV