Bioactive heterocycles containing endocyclic N-hydroxy groups

Abstract

Drug-likeness rules consider N-O single bonds as “structural alerts” which should not be present in a perspective drug candidate. In most cases this concern is correct, since it is known that N-hydroxy metabolites of branded drugs produce reactive species that cause serious side effects. However, this dangerous reactivity of the N-OH species generally takes place when the nitrogen atom is not comprised in a cyclic moiety. In fact, the same type of metabolic behavior should not be expected when the nitrogen atom is included in the ring of an aromatic heterocyclic scaffold. Nevertheless, heterocycles bearing endocyclic N-hydroxy portions have so far been poorly studied as chemical classes that may provide new therapeutic agents. This review provides an overview of N-OH-containing heterocycles with reported bioactivities that may be considered as therapeutically relevant and, therefore, may extend the chemical space available for the future development of novel pharmaceuticals. A systematic treatment of the various chemical classes belonging to this particular family of molecules is described along with a discussion of the biological activities associated to the most important examples.

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

“…23 For some drugs, including the histone deacetylase inhibitors trichostatin A and vorinostat, the N -hydroxyl group is a key pharmacophore required for target binding. 24,25 …”

“…In a similar manner to hydroxylamines, an oxime group can alter a natural product’s acid-base properties, solubility, and target binding. 24 Furthermore, the E/Z -geometry of an oxime can influence these features. 129 Early biosynthetic studies of oxime-containing natural products focused largely on plant glucosinolates, a family of N -hydroximinosulfate ester-containing metabolites which have anticancer activity.…”

Methyl Transfer in Glucosinolate Biosynthesis Mediated by Indole Glucosinolate O-Methyltransferase 5

“…Unsubstituted N-hydroxyindoles tend to be highly reactive (Acheson et al, 1974;Acheson, 1990;Somei, 1999). To stabilize these molecules, chemical groups withdrawing electrons from the electron-rich nitrogen of the N-hydroxy group or resonance-stabilizing substituents on the indole nucleus are required (Rani and Granchi, 2015). The conversion of the N-hydroxy group in 1OHI3M into an N-methoxy group, catalyzed by IGMT5, is such a stabilizing reaction.…”

Synthesis and spectral characterization of novel 1,5-benzodiazepine oxime derivatives

“…2 Thus, exocyclic (electron-poor) N-hydroxy compounds and heterocycles containing endocyclic N-hydroxy-portions have been used in the production of various types of bioactive molecules with enhanced metabolic stability, since they are less likely to generate reactive intermediates, such as nitrenium ions and nitrones. 3 Oximes (C=N-OH) belong to a broad class of N-hydroxy compounds and are known to be sources of nitric oxide (NO) -the key signaling molecule affecting the biology of living cells. 4 In 1998, R. F. Furchgott, L. J. Ignarro and F.…”