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conceitos de bioisosterismo-concentiso basicos para entendimento na area quimica, farmacia entre outros

1. OVERVIEW Bioisosteres are structurally related chemical subunits or groups which present broadly similar biological properties. Bioisosterism is a fundamental tactical approach to address a number of aspects associated with drug design and development. Bioisosteric molecular modifications can improve pharmacokinetic and pharmacodynamic properties of drug compounds. This study elucidates biological relevance of Bioisosteres in drug design by illustrating this approach in the improvement of Ibuprofen. 1

2. Ibuprofen is a widely used, common, over the counter NSAID (Non-steroidal anti-inflammatory drug),also an analgesic and an antipyretic . The use of Ibuprofen has adverse side effects like gastrointestinal (GI) damage , renal toxicity, cardiovascular disturbances and rarely reported neurological impairment. These toxic effects of the drug can be eliminated by bioisosteric replacements of the carboxylic acid moiety in the drug. 2

3. BIOISOSTERS 3

4. CARBOXYLIC ACID BIOISOSTERES Replacement of carboxylic acid group of compounds with a similar group. Biologically relevant compounds containing Carboxylic acid moiety: Arachidonic Pathway Inhibitors Angiotensin II Receptor Antagonists Excitatory Amino Acid Receptors Statins Fibrates NSAID 4

5. FUNCTIONS OF IBUPROFEN 5 Fig 1. Physiological Functions of Ibuprofen.

6. STRUCTURE Ibuprofen exists as a diasterioisomer , S (+) enantiomer: Prostaglandin synthesis inhibitor R (-) enantiomer: anti-inflammatory properties 40-60% of R enantiomer is metabolically converted to the form in liver and intestinal tract following oral absorption. 6 Fig 2. Structure of Ibuprofen.

7. PHARMACOKINETICS Oxidative metabolism occurs in two phases 7 Fig 3. Metabolism of Ibuprofen.

8. PHARMACODYNAMICS 8 Ibuprofen is a non-selective inhibitor of cyclooxygenase enzymes (COX1 and COX2) which convert arachidonic acid to prostaglandins mediators of pain, fever and inflammation. Anti-inflammatory, analgesic, anti-pyretic properties of ibuprofen are mainly due to inhibition of COX-2 which decreases synthesis of prostaglandins involved in mediating pain, swelling, fever and inflammation. Inhibition of COX-1 instead, results in toxic effects on the Gastrointestinal (GI) tract.

9. PHARMACODYNAMICS 9 Fig 4. Arachidonic acid pathway. (Courtesy: www.grepmed.com)

10. 10 Fig 5. Mechanism of Ibuprofen. (Courtesy: www.pharmagkb.com)

11. TOXICITY AND SAFETY 11 Fig 6. Gastrointestinal Toxicity of Ibuprofen. (Courtesy: tmedweb.tulane.edu)

12. 12 Fig 7. Docking of Ibuprofen with COX-1 enzyme. [7]

13. 13 BIOISOSTERISM IN IBUPROFEN Fig 8. Bioisosterism in Ibuprofen.

14. 1.Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with Ibuprofen 14 Fig 9. Anti-inflammatory activity results of the compounds. [5]

15. 15 Fig 10. Analgesic activity results of the tail-flick experiment. [5] Fig 11. Analgesic activity results of the hot plate experiment. [5]

16. 16 Fig 12. Ulcerogenic scores of compounds. [5]

17. 17 2. Oxetene, Thietane derivatives of Ibuprofen Fig 13. Inhibition of COX and 5-LOX pathways. [6]

18. 18 Fig 14. Concentration-response analyses of 5LOX-derived LTB4 and COX-derived PGE2/PGD2 inhibition by compounds 2 (top) and 10 (bottom). [6]

19. 19 CONCLUSION The effectiveness of the use of bioisosterism in ibuprofen drug modification to eliminate i ts adverse side effects has been successfully demonstrated, emphasizing the biological relevance of this approach. Bioisosteric substitution of the carboxylic acid moiety in ibuprofen can be carried out with other groups like tetrazole and sulphonamides . Sulphonamides , known for their anti-microbial properties can contribute further to the multi-functionality of Ibuprofen and eliminate its toxicity. Bioisosterism thus has enormous application in the biopharma industry for continual drug improvement and design .

20. 20 REFERENCES [1] Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. Journal of medicinal chemistry. 2011 Mar 17;54(8):2529-91. [2] Ershad M, Vearrier D. Ibuprofen Toxicity. InStatPearls [Internet] 2018 Sep 24. StatPearls Publishing. [3] Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology. 2009 Dec 1;17(6):275-342. [4] Rainsford KD. Ibuprofen: from invention to an OTC therapeutic mainstay. International Journal of Clinical Practice. 2013 Jan;67:9-20. 5]Uzgören-Baran A, Tel BC, Sarıgöl D, Öztürk Eİ, Kazkayası I, Okay G, Ertan M, Tozkoparan B. Thiazolo [3, 2-b]-1, 2, 4-triazole-5 (6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance. European journal of medicinal chemistry. 2012 Nov 1;57:398-406. [6] Lassalas P, Oukoloff K, Makani V, James M, Tran V, Yao Y, Huang L, Vijayendran K, Monti L, Trojanowski JQ, Lee VM. Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives thereof as bioisosteres of the carboxylic acid functional group. ACS medicinal chemistry letters. 2017 Jul 18;8(8):864-8. [7] Ahmed M, Azam F, Gbaj A, E Zetrini A, S Abodlal A, Rghigh A, Elmahdi E, Hamza A, Salama M, M Bensaber S. Ester prodrugs of ketoprofen: synthesis, in vitro stability, in vivo biological evaluation and in silico comparative docking studies against COX-1 and COX-2. Current drug discovery technologies. 2016 Mar 1;13(1):41-57.

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