Medicinal Chemistry Antimalarial drugs 4.pptx

Biguanides – biological transformation, SAR, metabolism, effects and side effects
Pyrimidines – site of action, SAR
Sulphones and sulphonamides – Action and toxicity
Mechanism of action of Antimalarials

1. Medicinal Chemistry-III A n timal a ria l a g e n ts 4 Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur , Amarkantak (M.P.) Dr. Akhilesh Tiwari Assistant Professor Department of Pharmacy, IGNTU, Amarkantak

2. Contents 2 Biguanides – biol o gi c al t r an s f orm a tion, S A R, m e t abolism, e f f e c t s and side effects Pyrimidines – site of action, SAR Sulphones and sulphonamides – Action and toxicity Mechanism of action of Antimalarials

3. At the end of this lecture, student will be able to Compare the structure with that of activity of antimalarials Discuss the biotransformation of specified antimalarials Describe the action and toxic effects of antimalarials Explain the synthesis of certain antimalarials Learning Objectives 3

4. Biguanid e s 4 Biguanides a r e p r odrug s f o r their dihydrotriazines (cyclized product) acti v e metabolites-the Biological transformation is illustrated with Proguanil (chlorguanide). The antimalarial agent formed in this instance is the drug cycloguanil , which itself is available as the pamoate salt, having a duration of action of several weeks to months.

5. Biotransformation of proguanil 5

6. Biguanid e s 6 SAR: - Substitution of a halogen on the para-position of the phenyl ring significantly increases activity e.g. Chlorine substitution in chloroguanil – The 4-bromine analog also is very active. A second chlorine at the 3-position of the phenyl ring of proguanil further enhanced the activity. However, the dichloro compound, chlorproguanil, is more toxic than chlorguanil .

7. Biguanid e s 7 Absorbtion, distribution and elimination: - They are absorbed very quickly from the GIT. They are concentrated in the liver, lungs, spleen & kidney but does not cross the blood brain barrier. 75% of the drug present in plasma is bound to protein They are metabolized and eliminated rapidly, mainly in the urine As a result, frequent administration of these drugs is necessary.

8. Biguanid e s 8 Toxicity: - Low toxicity, but with increased doses, haematuria (blood in urine) and albuminuria(albumin in urine) are observed Effects: - These derivatives including cycloguanil are potent schizonticides against both exoerythroctic & erythrocytic forms of P. falciparum and P. vivax. Resistance to these agents develops frequently.

9. Pyrimidines 9 Pyrimethamine Trimethoprim Th e me c hanis m o f ac t ion o f p yri m idines is di f f e r e n t a n d the i r structures are not related to quinine and aminoquinolines. Th e si t es o f action f o r these de ri v a ti v es include b ot h the e ry th r oc y tic f orm s o f P . vi v a x.

10. Pyrimidines 10 MOA Structurally, these derivatives resemble the pteridine portion of dihydrofolic acid (FH 2 ) And interfere with its reduction to tetrahydrofolic acid (FH 4 ) by dihydrofolate reductase, thereby interfering with the utilization of folic acid (in malarial protozoa) Pyrimethamine & trimethoprim are used in suppressive treatment and as radical cure agents.

11. Pyrimidines 11 SAR: - M a x i mum a ctivity is o b t ained wh e n an el e c t r on-don a ting g r oup was present in the 6-position e.g alkyl. When a chlorine atom is present in the para-position of the phenyl ring a maximum activity is obtained. If the two rings are separated by either an oxygen atom or a carbon atom, antimalarial action is decreased. Eg. Trimethoprim

12. Pyrimidines 12 ADME : - Pyrimethamine is slowly but completely absorbed from the G.I.T. It is localized in the liver, the lungs, the kidney & the spleen. It is completely metabolized It is slowly excreted through the urine. Trimethoprim has a shorter half-life (24hrs) than pyrimethamine. Toxicity: - P y rim e tha m ine is r el a t i v ely no n t o xi c , bu t o v e r do s es m a y le a d to depression of cell growth by inhibition of folic acid activity.

13. S u l f ones 13 Dapsone:- 4,4’- diaminodiphenyl sulfone has a prophylactic activity a g ain s t r esi st a n t P . f alciparu m . It is was developed for the treatment of leprosy. Dapsone act by competing with PABA, in the synthesis of folic acid. Dapsone has a prolonged duration of action and a moderate toxicity. Combination with pyrimethamine have been effective in suppressing symptoms of malaria due to chloroquine-resistant P. falciparum.

14. Sulfonamides 14 Sul f onamide s a r e use d in a n tim a lari a l resistant malarial strains. Th e y a r e e f f e c ti v e a g ain s t e r y th r oc y t i c protozoa. Medium or long-acting sulfonamides the r a p y against dru g- s t a g es o f the mal a r i a l a r e use d cli n i c ally as antimalarials particularly sulfadiazine, sulfadoxine and sulfalene. E ach o f the ab o v e sul f onamide s a r e mu c h m o r e e f f e c ti v e when given in combination with pyrimethamine.

15. Sulfonamides 15 Sulfadoxine: - Sulfalene: - Sulfadiazine: -

16. Ar t esu n a t e 16 Artesunate is a medication used to treat malaria. The intravenous form is preferred to quinidine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine or amodiaquine. It is not used for the prevention of malaria

17. Ar t em e ther 17 Artemether is used to treat acute uncomplicated malaria. It is administered in combination with lumefantrine for improved efficacy. This combination therapy exerts its effects against the erythrocytic stages of Plasmodium spp. and may be used to treat infections caused by P. falciparum and unidentified Plasmodium species.

18. Atovaquone 18 A t o vaqu o n e is a nap h thoquin o n e use d f o r the p r e v e n tion and treatment of Pneumocystis pneumonia (PCP) and, in combination with proguanil, used for prevention and treatment o f P . f alciparum mal a ria

19. Classification based on MOA Antimalarials can be divided into two classes based on their MOA 1) The first class of compounds are characterized by rapid onset of schizoticidal action Includes the cinchona alkaloids, aminoquinolines and acridines and involves a relatively non-specific mechanism. The derivatives in this first group inhibit nucleic acid and protein synthesis in the protozoal cell. Due to the interaction between the drug and DNA. 19

20. Antimalarials- based on MOA contd…. 20 The flat aromatic quinoline or acridine ring can position or intercalate between the base pairs in the DNA-α-helix and the secondary alcohol group in quinine or the amino groups in the other derivatives provide secondary binding through hydrogen bond formation. Because these events can take place in mammalian host cells as well as in parasite cells, The antimalarial action depends upon selective accumulation of the drugs in the parasite cell.

21. Antimalarials- based on MOA contd…. E.g chloroquine, erythrocytic schizonts can concentrate the drug to a level many times that of the plasma concentration. Host cells require a 100-fold greater concentration to be affected than is necessary to kill parasite cells. 21

22. Antimalarials- based on MOA contd…. 22 2) The second class includes the pyrimidines, biguanides and sulfones and involves interference with the synthesis of tetrahydrofolic acid (FH 4 ). This mechanism is characterized by a slowly developing schizonticidal action dependent upon the stage of multiplication of the parasite. The pyrimidine and biguanide derivatives are competitive inhibitors of dihydrofolic acid (FH 2 ), binding to dihydrofolate reductase and thereby interfering with conversion of FH 2 to FH 4 . FH 4 is necessary for the synthesis of purines and thymidine.

23. Antimalarials- based on MOA contd…. 23 The effect occurs in host as well as in parasite cells, but is selective to the parasite because of a greater effective concentration. The sulfones as well as sulfonamides interfere with the synthesis of dihydrofolic acid by competing with p-amino benzoic acid (PABA) incorporation. The metabolites of the sulfones resemble PABA structurally and when incorporated, produce an inactive coenzyme. This mechanism does not operate in mammalian host cells.

24. Summary 24 Biguanides – biol o gi c al t r an s f orm a tion, S A R, m e t abolism, e f f e c t s and side effects Pyrimidines – site of action, SAR Sulphones and sulphonamides – Action and toxicity Mechanism of action of Antimalarials