1. CLICK CHEMISTRY AND DRUG DISCOVERY
Dr. (Mrs). Ana G. Nikalje Professor and Head Department of Pharmaceutical Chemistry Y. B. Chavan College of Pharmacy, Aurangabad
Maharashtra, India

2. CONTENT Introduction Click reactions In situ click chemistry
Click chemistry and biconjugation
Conclusion

3. INTRODUCTION
The way organic synthesis is done has pervasive effects on entire process of drug discovery, development and manufacture.
Thus, the way that drug discovery is performed today requires more time and money which lead to expensive drugs.
Combinatorial chemistry is even more dependent than ‘traditional’ synthetic chemistry on the reliability of the individual reactions used to construct the new network of chemical bonds.
Click chemistry is new approach to synthesis that greatly facilitates this process, making use of few near- perfect chemical reactions.

4. Defining a Click chemistry reaction by sharpless point of view
A click reaction must be modular, wide in scope, high yielding, create only inoffensive by-products (that can be removed without chromatography), are stereospecific, simple to perform and that require benign or easily removed solvent

5. A CLICK REACTION would be modular be wide in scope
give very high yields
generate only inoffensive products
be sterospecific (not necessarily enatioselective)
required simple reaction conditions
required readily available reagents and starting materials

6. required no or benign solvent or easily removable solvents
required a simple product isolation and purification (no flash)
gives product that are stable in physiological conditions
be atom economic
have a high thermodynamic driving force (<20 kcal-mol

7. ‘CLICK’ reactions
Cycloaddition reactions, especially from the 1,3- dipolar family, but also hetero-Diels-Alder reactions
Nucleophilic ring-opening reactions, especially of strained heterocyclic electrophiles, such as epoxides, aziridines, cyclic sulfates, cyclic sulfamidates, aziridinium ions and episulfonium ions
Carbonyl chemistry of the non-aldol type (e.g. the formation of oxime ethers, hydrazones and aromatic heterocycles)
Addition to carbon–carbon multiple bonds; particularly oxidation reactions, such as epoxidation dihydroxylation, aziridination and nitrosyl and sulfenyl halide additions, but also certain Michael addition reactions.

8. Fig. Click Chemistry – energetically highly favorable linking reactions
Unsaturated compounds provide the carbon framework. New groups are attached via carbon-heteroatom bonds (shown in red)

9. Cycloaddition reactions
1,3-dipolar cycloaddition reactions
The copper-(I)-catalyzed coupling of azides and terminal acetylenes creates 1,4-disubstituted 1,2,3-triazole linkages, which share useful topological and electronic features with nature’s ubiquitous amide connectors
Synthesis of triazole from amides

10. Examples of Copper Catalyzed Azide/Alkyne Cycloaddition (CuAAC)
e.g. Inhibitors of HIV-Protease by CuAAC
HIV-Protease cleaves proteins to yield active HIV virus
Amprenavir is HIV-protease inhibitor used clinically since 1997.
Develop Amprenavir analogue using CuAAC for combinatorial screening

11. Synthesis of HIV Protease Inhibitor

12. Continues..

13. Nucleophilic ring-opening reactions

14. Nucleophilic ring-opening reactions

15. Carbonyl chemistry of non-aldol type
CLICK reactions of non-aldol includes
Synthesis of oximes
Synthesis of hydrazones
Synthesis of aromatic heterocycles

16. Addition to carbon–carbon multiple bonds
Addition to carbon-carbon multiples bonds includes following reactions
Epoxidation
Dihydroxylation
Aziridination

17. Epoxidation

18. Dihydroxylation

19. In situ Click chemistry
The enzyme AChE catalyzes the formation of its own inhibitor. Whereas the less active anti-triazole (anti-6), which is not formed in situ, does not alter the conformational state of the enzyme, the highly potent syn- triazole (syn-6), formed in situ, traps the enzyme in a ‘new’ conformational state, which is probably a low abundance one in the absence of syn-6.

20. In situ Click chemistry

21. Click chemistry and bioconjugation
In vivo and in vitro bioconjugation applications benefit from the unprecedented reliability of the copper-catalyzed azide–acetylene union, the inertness of the reactants under physiological conditions, and the mild reaction conditions.
Applications are
Tagging of live organisms and proteins
Activity-based protein profiling (ABPP)
Labeling of DNA

22. Virus, cell and protein tagging
in vivo activity-based protein profiling

23. DNA labeling to enable sequencing by Sanger di-deoxy chain termination reaction

24. Conclusion
In summary, click chemistry has proven to be a powerful tool in biomedical research, combinatorial chemistry, in situ chemistry for lead discovery and bioconjugation and DNA research
Promise to accelerate both lead finding and lead optimization, due, above all, to its great scope modular design, and reliance on extremely short sequences of near-perfect reactions
Nice concept to facilitate drug discovery