Bibliografía

The benzimidazole nucleus is a vital core in many compounds acting at different targets to cause a range of pharmacological effects. However all seven positions in the benzimidazle nucleus can be substituted with different chemical units, but in the most of the biologically benzimidazole based compounds functional groups are located at the 1, 2, 5 or 6 positions. Therefore, the compounds might be mono-, di- or tri-substituted derivatives of the nucleus. Suitably substituted benzimidazole derivatives have established different therapeutic applications such as in antimicrobial ³⁹ antiviral, antifungal, anticancer, antiulcer, antihypertensive and antihistaminics1.^29,42,43

The optimization of benzimidazole-based structures led to several drugs which are presently on the market.(Figure 4).²⁸

14 Figure 4. Benzimidazole-based structures drugs.²⁸

1.2.3. Triazole in medicinal chemistry

Triazole is one of the organic heterocyclic compounds consisting of a five-membered ring structure.

It contains three nitrogen atoms and two carbon atoms. Triazole is pale yellow crystalline solid which is soluble in water and alcohol. It exists as a pair of isomeric compounds, 1,2,3-triazole 28 and 1,2,4-triazole 41 (Figure 5) depending on whether the carbon atoms are adjacent or not.^43,44,45

15 Figure 5. Pair of triazole isomers.

This unique structure of triazole allows its derivatives to freely bind with a range of receptors and enzymes in biological systems and to show an extensive spectrum of biological activitiy.^46-48 Moreover, the triazole ring can be combined with different pharmacophore groups to create novel drug molecules as an attractive linker. Therefore it provides a useful and effective pathway to develop different bioactive molecules.^49-51

Triazole based compounds with pharmacological activity indicated some advantages such as low toxicity, high bioavailability, less multi-drug resistance, broad spectrum activity, better therapeutic effect, and fewer adverse effects. Therefore they have been regularly applied in the treatment of different types of disease including cancer.^52-54 In general, triazole derivatives have various pharmacological activities such as antifungal, antihistaminic, antimicrobial, anti-inflammatory, and antineoplastic. in addition to anticancer activities which is a major target for medicinal chemists (Figure 6).^43,55

16 Figure 6. Examples of antitumor triazole-base compounds in vitro.⁴³

1.2.4. Benzotriazole in medicinal chemistry

Benzotriazole 45 is another of the important scaffolds found in many biologically active compounds and drugs. It is an inexpensive, non-toxic, highly stable, aromatic nitrogen heterocycle consisting of a benzene ring fused to a triazole. Benzotriazole can be produced by diazotization of one the amine groups in benzene-1,2-diamine 36 with sodium nitrite and an acid (often a carboxylic acid) (Scheme 9). The reaction is usually best conducted at lower temperature (5-10 ᵒC) to avoid loss of nitrous acid or decomposition of the unstable diazonium intermediate.^56-59

17 Scheme 9. Synthesis of benzotriazole.⁵⁹

Benzotriazole, because of its fused, more highly conjugated structure, can form stronger π-π stacking interactions compared to triazole. In addition, the three nitrogen atoms allow it to form coordination and hydrogen bonds easily. Therefore the benzotriazole-based compounds can bind to enzymes and receptors in biological systems more easily through different non-covalent binding modes which results in an extensive spectrum of biological activity. Moreover, benzotriazole can form BTA-containing metal complexes by binding the benzotriazole nucleus to different metal ions which could exert a double action mechanism to overcome drug resistance, due to both benzotriazole derivatives themselves and their supramolecular agent activity.⁶⁰ For the above reasons, the benzotriazole moiety has been regularly employed to design novel drug molecules.^61-63

Recently, medicinal chemists working on benzotriazole derivatives have reached great improvement.

They have discovered a number of BTA-base compounds with effective pharmacological properties, low toxicity, few side effects, little multi-drug resistance, good water solubility, promising bioavailability, diversity of drug administration, as well as a broad bioactivity spectrum.^62-64

Generally, bioactive BTA-based compounds are being extremely investigated all over the world to treat different types of disease including cancers.

Some anticancer benzotriazole derivatives such as Vorozole and TBB have been in clinical use (Figure 7). The successful examination of these drug encourages continuation of work to make the new BTA-based anticancer compounds targeting different kinases or receptors.^65-68

18 Figure 7. Examples of clinical antitumor BTA-based compounds.

1.2.5. Reactions of Perfluorinated Arenes and Heteroarenes

Examining fluorinated arene and heteroarene systems for the chemical synthesis of a wide range of polyfunctional carbo- and hetero-cyclic derivatives, has been one of the early research programs that has been pursued in organofluorine chemistry since the 1960s. For synthesis of a wide range of highly functionalised heteroaromatic and ring fused polycyclic systems, perfluoroarenes such as pentafluoropyridine, and hexafluorobenzene can be used as core scaffolds.⁶⁹

Reaction of a perfluoroaromatic as an acceptor moiety with various nucleophiles as the donor moiety involves nucleophilic aromatic substitution (SNAr) and occurs readily under usually mild conditions.

The reaction can involve displacement of fluorine from highly fluorinated aromatic systems by carbon, nitrogen, oxygen and sulphur centred nucleophiles, due to the strong electron withdrawing effect of the fluorine substituents, rendering the compounds extremely sensitive towards nucleophilic attack.

The majority of reactions of perfluoroaromatic systems proceed by the two-step addition-elimination nucleophilic aromatic substitution (S_NAr) mechanism. The first step of the reaction involves the flouting of the aromaticity of the fluoroaromatic ring and creation of a tetrahedral intermediate (the

19 so-called Meisenheimer intermediate). The Meisenheimer intermediate usually breaks down quickly through the ejection of a fluoride ipso to the site of initial nucleophilic attack therefore aromaticity is recouped (Scheme 10). ⁷⁰