E. A. Chugunova

The Properties and the Use of Substituted Benzofuroxans in Pharmaceutical and Medicinal Chemistry: A Comprehensive Review

Since the synthesis of 4,6-dinitrobenzofuroxan in 1899 by Drost, benzofuroxans have attracted particular attention. This peculiar series of compounds exhibit a broad spectrum of biological activity including antibacterial, antifungal, antileukemic, acaricide and immunodepressive properties. These works embrace a period of more than 50 years since the pioneering paper of Gosh and Whitehouse and papers in this major field of the heterocyclic chemistry are still published in 2013. The review has been built in two independent parts. The first one is directly dedicated to the structure of substituted benzofuroxans and will show many medicinal applications of these compounds such as nitric oxide-releasing abilities, induction of oxidative stress, potent anti-cancer agents, anti-chagas agent, target for antiamoebic agent, Ca2+ channel blockers or cytotoxic, mutagenic and genotoxic agent… The second part of this review will be in close connection with the use of benzofuroxans as synthetic precursors in the preparation of new biological compounds such as quinoxaline dioxide, benzimidazole and phenazine derivatives. The interaction of substituted benzofuroxans with electron rich heterocycles or carbanions is the key step in the synthesis of these new biological active compounds. These derivatives can be used as cytotoxic drugs, antimycobacterial agent and display anti-malarial, antileishmanial and antituberculosis activity. The nature of the substituent linked to the carbocyclic ring of benzofuroxan is of primary importance to understand the medicinal properties of this family of compounds. For example, when benzofuroxans are substituted by electron-releasing substituents, the chemical reactivity is transferred from the carbocyclic ring to the furoxan ring.

Synthesis and antimicrobial activity of novel structural hybrids of benzofuroxan and benzothiazole derivatives

New compounds containing both benzofuroxan and benzothiazole scaffolds were synthesized through electrophile/nucleophile combination of nitrobenzofuroxan derivatives and 2-mercapto- or 2-aminobenzothiazole derivatives and their biological effect on the natural strain Vibrio genus and different bacterial lux-biosensors was studied. Among all the compounds synthesized, that obtained from 2-mercaptobenzothiazole and 7-chloro-4,6-dinitrobenzofuroxan was toxic for bacterial cells, and also able to activated the 1st type Quorum Sensing system. The reaction between 7-chloro-4,6-dinitrobenzofuroxan and 2-aminobenzothiazole derivatives gave two products, one bearing the benzofuroxan moiety linked to the exocyclic amino nitrogen, and the second derived from the attack of two molecules of electrophile to both the nitrogen atoms of the benzothiazole reagent. Their relative ratio is modifiable by tuning the reagents ratio and the reaction time.

Synthesis of the first tertiary ammonium derivative of 6-chloro-5-nitrobenzofuroxan

Benzofuroxans occupy an important place among a variety of compounds possessing high biological activity [1, 2]. In recent time, interest in benzofuroxans has considerably increased due to discovery of new kinds of biological activity in this series of compounds, in particular antiparasitic, antibacterial, and antifungal activities of benzofuroxans have been reported. Design of new compounds on the basis of nitrobenzofuroxans seems to be quite promising, taking into account their high intrinsic fungicidal and bactericidal activity, the lack of toxicity and genotoxicity, and various protective biological effects [3, 4]. Other important biologically active compounds are ammonium salts which are widely used in biology, medicine, chemistry, and pharmacy. Potential medicinal applications of ammonium salts are very wide; for example, they are used as antiseptics and disinfecting agents for medical equipment [5].

Synthesis, Genotoxicity and UV-protective Activity of New Benzofuroxans Substituted by Aromatic Amines

The synthesis of new organic compounds possessing properties, which can be used for biological or pharmaceutical purpose, is very challenging and is a current trend in heterocyclic chemistry. So benzofuroxans are of great interest from a medical and combinatory chemistry point of view, being effective biologically active compounds. They are easily available, easily tuned and functionalized allowing the creation of databases in which a chemist can find proper informations to prepare the structurally appropriate compound with the requested selective effect. In this work, heterocyclic compounds are prepared on the basis of the interaction of 4,6-dichloro-5-nitrobenzofuroxan with aromatic amines and diamines. Their ability to suppress and prevent genotoxic effects of UV-radiation in the wavelength range between 300-400 nm has been studied. It has been shown that these compounds are able to protect bacterial cells from destructive effects of the UV-radiation. Comparing the results obtained for various benzofuroxans to those obtained for the natural antioxidant  - tocopherol (vitamin E) and for the synthetic antioxidant trolox, which are references in this domain, we have shown that some benzofuroxans quantitatively exhibit a similar protective effect, and that compounds prepared from the reaction between 4,6-dichloro-5-nitrobenzofuroxan and ethylenedianiline possess potent protective potential.

Synthesis of amino acid derivatives of benzofuroxan

149 Furoxans (derivatives of 1,2,5 oxadiazole N oxide) are heterocyclic thermally stable compounds. Furoxans can slowly produce NO for a long time and do not cause devel opment of nitrate tolerance [1]. In the design of hybrid pharmaceuticals, they are often introduced as an NO producing fragment into the molecule of a known prepa ration to impart it with, for example, cGMP dependent vasodilation or antiaggregatory properties [1–3]. One of the recent directions in medicinal chemis try is the design of hybrid multifunctional pharmaceu ticals that combine two or more pharmacophores in one molecule. The wide spectrum of pharmacological activity of these pharmaceuticals, the ability of drug to interact with several targets, is matched against selectivity. Amino acids are often used as an addi tional pharmacophore [4]. Amino acids can behave as both independent pharmacophores and linkers for the attachment of an additional pharmacologically active fragment due to the presence of a free carboxyl group.

Synthesis of new 3H-benzo[1,2,5]oxadiazine-4-oxides with heterocyclic moieties in the benzene ring

Synthesis of New 3H-Benzo[1,2,5]oxadiazine-4-oxides with Heterocyclic Moieties in the Benzene Ring E. A. Chugunova*, N. I. Akylbekov, N. V. Gavrilov, V. A. Samsonov, S. A. Sitnov, A. B. Dobrynin, M. A. Pudovik, and A. R. Burilov a Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences, ul. Akademika Arbuzova 8, Kazan, Tatarstan, 420088 Russia *e-mail: elena-chugunova@list.ru b Kazan National Research Technological University, Kazan, Tatarstan, Russia c Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia d Kazan Federal University, Kazan, Tatarstan, Russia

Synthesis of New ‘Hybrid’ Compounds Based on Benzofuroxans and Aminoalkylnaphthalimides

Pathogenic bacteria and fungi eventually develop resistance to existing drugs, and therefore, we need constant development of new drugs. The research is aimed at addressing fundamental scientific problems—the search for new biologically active compounds among several benzofuroxan‐containing ‘hybrid’ products. N‐substituted naphthalimides were chosen as a second pharmacophore. Benzofuroxanes biological effects were studied by means of bacterial lux‐biosensors. Compounds IIIa, IVa, IIIc, and IVc displayed more expressed bacteriotoxic action in comparison with the initial substances Ia‐c and represent a certain interest for using as antibacterial substances.

Reactions of benzofuroxans with aminoalkyltriphenylphosphonium bromides

Herein we report on studies involving super electrophilic benzofuroxans: 4,6-dichloro-5-nitrobenzofuroxan IIa, 7-chloro-4,6-dinitrobenzofuroxan IIb, and 5,7-dichloro-4,6-dinitrobenzylfuroxan IIc. Those compounds contained electron-withdrawing nitro groups increasing the reactivity of benzofuroxans towards nucleophiles and easily eliminating chlorine atoms allowing modification of the molecules with various pharmacophore moieties [2].

Photochromism of 3 H -2,1,4-benzoxadiazine 4-oxides with heterocyclic substituents on the benzene ring

Abstract2H-Benzimidazole 1,3-dioxides undergo thermal isomerization to 3H-2,1,4-benzoxadiazine 4-oxides which are converted to 2H-benzimidazole 1-oxides on further heating. Irradiation of 3H-2,1,4-benzoxadiazine 4-oxides with sunlight induces their transformation to 2H-benzimidazole 1,3-dioxides. 3H-2,1,4-Benzoxadiazine 4-oxides containing nucleophilic heterocyclic substituents are considerably more stable to sunlight, and they can be used as photochromic compounds.

Novel Structural Hybrids on the Base of Benzofuroxans and Furoxans. Mini-Review

Hybrid drug strategy is based on the combination of two or more pharmacophores into a new chemical entity to improve the properties of the original compounds or to obtain double action of resulting molecule. Hybrid molecules, comprised of some pharmacophore and nitric oxide (NO) donor moiety, constitute one of the more promising approaches for the design of drugs. Furoxans and benzofuroxans are considered NO releasing prodrugs and are of great interest for researchers. In this review we will focus on furoxan and benzofuroxan hybrids described in literature during the last years (from 2005 to 2016).