Synthesis and Characterization of Bioactive Heterocyclic Molecular Hybrids

The increasing interest on new drug discovery is frequently advanced as drugs do not increase endurance adequately against increasing cancer cases worldwide. Molecular hybridization is a new concept in drug design and growth based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with enhanced affinity and efficacy, when compared to the parent drugs

1. The Molecular Hybridization is a approach of normal design of new ligands or prototypes based on the detection of pharmacophoric sub-unities in the molecular structure of two or more known bioactive derivatives which, through the ample fusion of these sub-unities, lead to the design of new hybrid architectures that maintain pre-selected characteristics of the original templates. Literature survey revealed that the history of heterocyclic chemistry began in the 1800's, in step with the development of organic chemistry. After World War II, there was a massive explosion research in the field of heterocycles. About one half of over six million compounds recorded in Chemical abstract are heterocyclic. Considering the use of known model a substances, already evaluate concerning the physicochemical and pharmacological features, toxicity and mechanism of action
2. Triazole moiety is a significant and recurrent insecticide, agrochemical structure feature of many biological active compounds as cyto-crome enzyme inhibitors and peptide analog inhibitor. The azole class of antifungal agent is chemical either a triazole or an imidazole group attached to an asymmetric carbon atom as their functional pharmacophore treatment for these infection azole like antifungal agent are Fluconazole, Ketoconazole, and Ptraconazole 1, 2, 4-triazole, Voriconazole are as pain reliever antiasthmatic, anticholinergic activity, antibacterial
3. At the present time, cancer has progressively become the foremost cause of death all-inclusive and seriously endangering the health and existence of humans for a long era. It has been reported that cancer can be caused by one of the three ways namely, incorrect diet, genetic predisposition and environmental contaminants
4. The pyrimidines and there derivatives have also been considered since past century as they also hold a diverse pharmacological properties and a spacious range of biological activities against unrelated DNA and RNA, diuretic, antitumor, viruses including polio herps viruses, anti HIV, cardiovascular and so on
5. The features possessed by the 1,2,3- triazoles make them pharmaceutically significant molecules. They are stable to reduction and oxidation as well as to hydrolysis in acidic and basic conditions, which indicates their high aromatic stabilization. 1,2,3-triazoles have a high dipole moment (about 5 D) and are able to contribute actively in hydrogen bond formation as well as in dipole-dipole and π stacking interactionswhich helps them in binding easily with the biological targetsand improves their solubility. The click chemistry approach invented by Sharpless using copper (I)-catalyzed azidealkyne cycloaddition (CuAAC) has resulted in the production of large number of 1,4-disubstituted 1,2,3-triazoles in very high yields.
6. Cancer is a group of diseases where the cells grow abnormally and multiply through uncontrolled cell division. Cancer cells are more metabolically active than normal cells. It gradually invades and destroys nearby normal cells by forming a lump called a tumour. Not all tumors or lumps are benign tumors are not cancer. It is localized and of small size that tends to grow quite slowly. It does not spread to other parts of the body and is rarely life threatening.

Both external and internal factors such as dietary fat intake, solvent and pesticide exposure, exposure to ionizing radiation (causing acute leukemias, thyroid cancer, breast cancer, lung cancer and others), smoking cigarette, some virus (HIV, HPV and Hepatitis B virus) and unhealthy lifestyle (being overweight, inadequate physical exercise, in excess of alcohol, insufficient vegetables and fruit, extra sugar and red meat) can cause cancer. Once the DNA is affected, there are no normal control systems that prevent cell overgrowth and the invasion of other tissues in cancer cells. Cancer is one of the most widespread and leading deadliest disease, and suffers one third of the world’s population by this disease. Thus molecule containing Triazole moiety show anti- Cancer activities and might be able to protect the drug resistance to certain extent Cefatizine, anti-bacterial agent Tazobactum as well as anti-cancer agent7. In this review, we focus on the most relevant advances recorded of click chemistry reactions and synthesis under mild physiological conditions and with high efficiency and chemoselectivity.

Literature review

Chalcones and its derivatives are attracted increasing attention due to numerous pharmacological applications. They are main precursors for the biosynthesis of flavonoids and exhibit various biological activities such as anti-cancer, anti-inflammatory, nitric oxide regulation and anti hyperglycemic agents. In recent years, ionic liquids have been emerged as a powerful alternative to conventional molecular organic solvents due to their particular properties, such as undetectable vapor pressure, wide liquid range, as well as ease of recovery and reuse, and making them a greener alternative to volatile organic solvents. Chalcones are having broad range of biological activity and are bring into being to be effectual as antibacterial, anti-inflammatory, antifungal and anticancer etc. Chalcones are on the whole the α,β unsaturated carbonyl compounds in which it contain ketoethylenic group.

Chalcones have conjugated double bonds and a entirely delocalized π-electron framework on both benzene ringsThe chemistry of chalcones has generated intensive scientific studies throughout the world. Especially interest has been focused on the synthesis and biodynamic activities of chalcones. The name “Chalcones” was award by Kostanecki and Tambor. These compounds are also known as benzalacetophenone or benzylidene acetophenone. In chalcones, two aromatic rings are linked by an aliphatic three carbon chain. Chalcone bears a very good synthon so that variety of novel heterocyclic with good pharmaceutical profile can be designed. Different methods are available for the preparation of chalcones8. Chalcones have a simple chemistry which enables a multiplicity of substitutions with easy synthesis. Currently, a variety of methods and schemes are available for the synthesis of chalcone derivatives. In each of these methods, the most important part is condensation of two aromatic systems (with nucleophilic and electrophilic groups) to yield the chalcone scaffold. Despite the multiplicity of substitutions allowed, we describe below the reaction scheme using the standard scaffold of chalcones (1,3-diphenyl-2-propen-1-one).

1. 1. Claisen-Schmidt condensation

The Claisen-Schmidt condensation is one of the most common. In this reaction, chalcones are formed by condensation of benzaldehyde and acetophenone derivatives in the presence of alkaline or acid catalysts in liquid solvent at 50–100 °C for several hours. The conventional Claisen-Schmidt reaction is typically carried out in the liquid phase, but certain reactions can take place in the solid phase (e. g. , acetophenone derivatives are primarily bound to the resin and then treated with benzaldehyde derivatives) or solvent-free phase (e. g. , condensation in the presence of catalyst triazabicyclodecene). In addition, the use of microwaves in liquid and solvent-free Claisen-Schmidt reactions reduces synthesis time and yields good amounts of chalcones8.

1. 1. Coupling Reaction

Chalcones also are synthesized by a coupling reaction between benzaldehyde andphenylacetylene in the presence of HBr and ionic liquids, such as 1-butyl-3-methyl-1H-imidazolium 4-methylbenzenesulfonat for 12 h at 100 °C 9.

1. 1. Carbonylative Heck Coupling Reaction

In the carbonylative Heck coupling reaction chalcones are synthesized by carbonylative vinylation of phenyl halide with styrene in the presence of carbon monoxide and using palladium (Pd) as catalyst.

1. 1. One-Pot Synthesis

The one-pot synthesis is a simple, yet efficient green method which allows synthesis of chalcones in just one reactor. This method provides several advantages, such as increased reaction efficiency, and avoidance of the lengthy purification process of the intermediate chemical compounds, in this manner saving resources and time. The reaction consists of a mixture of phenylmethanol and acetophenone in the presence of the oxidizing agent CrO3.

In this reaction, CrO3 plays the vital role of generating the benzaldehyde from phenylmethanol, which further reacts with the acetophenone to produce the desired chalcone. Bioactivity of triazole Nucleu. Click chemistry of 1,2,3- Triazole 45. 1,2,3-Triazole is a well known important heterocycle both in synthetic as well as medicinal chemistry due to its simple synthesis via click chemistry approach and a wide range of biological activities. Simple copper catalyzed 1, 3-dipolar cycloadditions of substituted azides and alkynes afford regioselective 1, 4-disubstitued 1, 2, 3-triazoles with high yields. 1, 2, 3-Triazole with high dipole moment, considerable stability and capability for hydrogen bonding make it a favorable binder of biomolecular targets. 1,2,3-Triazole derivatives were reported to exhibit various biological activities such as antidiabetic, antitubercular, anti-inflammatory, antifungal, antiviral and antibacterial. Several drugs like carboxyamidotriazole, cefatrizine, and tazobactam bear 1,2,3-triazole in their structure.

1. Since Sharpless and co-workers’ seminal report onso called ‘click chemistry’ concept, a huge number of papers havebeen published on the use of the prototypical click reaction constituted the copper(I)-catalyzed azide-alkyne cycloaddition(CuAAC) to give under mild conditions 1,4-disubstituted 1,2,3- triazoles in very high yields. This metal-catalyzed reaction discovered independently in the Sharpless and Meldal laboratories
2. Click chemistry is a modular synthetic approach towards the assembly of new molecular entities. This strategy relies mainly upon the construction of carbon-heteroatom bonds using spring-loaded reactants. The wide scope of CuAAC is firmly demonstrated by the use in different areas of life and material sciences such as drug discovery bioconjugation, polymer and materials science, and related areas including supramolecular chemistry
3. The 1,2,3-triazole core has been applied in many synthetic organic chemistry approaches. This heterocycle exhibited a broad range of efficient biological activities. Moreover, 1,2,3-triazole derivatives are shown to possess a diversity of interesting biological activities, including anti-HIV and hepatitis C, anti-allergic, antifungal, anti-tubercular, anti-inflammatory agents, and antimicrobial. Scheme1. One of the most popular methods to prepare 1,2,3-triazoles is the cycloaddition of alkyl azides with terminal alkynes via 1,3-dipolar cycloaddition reaction – the Huisgen reaction – as a regioisomeric mixture of the 1,4- and 1,5-disubstituted ones. This reaction was further developed by Meldal and Sharpless. They discovered that the use of copper (I) as catalyst guarantees a high regioselectivity and excellent yield allowing exclusively the 1,4-regioisomer. The copper-catalyzsed azide– alkyne cycloaddition (CuAAC) has thus fascinated attention for use in a variety of applications
4. Scheme 2A simple efficient, and mild method for the synthesis of substituted 1,2,4-triazoles from hydrazines and formamide proceeds smoothly under microwave irradiation in the absence of a catalyst and shows excellent functional-group tolerance
5. In a typical experiment, weighed 10 m-mol benzaldehyde, 10 mmol acetophenone, and 2. 0 mmol ionic liquid TSILs were mixed in a 25 mL round-bottom flask equipped with a distillation condenser. The reaction was typically allowed to proceed for a length of time at desired temperature with the vigorous stirring under N2 atmosphere (Scheme 4), the resulting mixture became biphasic system when stilled for several minutes, and the upper product phase was separated from the catalyst by decantation or extracting by CH2Cl2. The catalyst was extracted with CH2Cl2 and dried in a vacuum for 2 h before reusing. The product was purified by recrystallization from ethanol and identified by 1H NMR, and physical data (m. p) with those reported in literature
6. Modes of action of triazole moietyIn principle, drug resistance to chemotherapy remains to be a major impediment to the successful treatment of cancer. Therefore, the discovery of new chemical entities with the ability to overcome the drug resistance in tumor cells is likely to improve the therapeutic index. This showed promising IC50 values ranging from 0. 7e 1. 2 mM respectively We further evaluated thein vitro antiproliferative activity of the most potent compound 4 against another six tumor cell lines, which derived from differenthuman tissues, including glioma (U251), breast (SKBR-3), lung(A549), colon (HCT-116), hepatoma (SMCC-7721) and prostate (LNCaP). The result showed that compound 24 strongly inhibitedthe growth of all the tested cancer cells, exhibiting IC50 values ranging from 0. 6 to 1. 8 mM. Meanwhile, the IC50 values in normal human foreskin fibroblast (HFF) and human liver (HL-7702) cells were 5. 4 mM and 7. 8 mM respectively, implying there was a therapeutic window to use compound 416.