Medicinal Chemistry Antimalarial drugs 2.pptx

Biguanides (PCC)
Proguanil
Chloroproquanil
Cycloguanil
Sulphones (D)
Dapsone
Polycyclic antimalarial drugs (HD)
Doxycycline
Halofantrine
Pyrimidines (PT)
Pyrimethamaine
Trimethoprim

1. A n timal a ria l a g e n ts - 2 Department of Pharmacy 1

2. Contents 2 Classification of Antimalarials Structural Activity Relationship, pharmacokinetics, pharmacological effects and side effects n of the following: cinchona alkaloids 8- aminoquinolines 4- aminoquinolines 9- acridines

3. At the end of this lecture, student will be able to Classify Antimalarials Compare the structure and activity relations of Antimalarials Discuss the metabolism, effects and side effects of Antimalarials 3 Learning Objectives

4. Classification 4 Biguanides (PCC) Proguanil Chloroproquanil Cycloguanil Sulphones (D) Dapsone Polycyclic antimalarial drugs (HD) Doxycycline Halofantrine Pyrimidines (PT) Pyrimethamaine Trimethoprim BSPP N CAAA KA VIRODH NAHI KIYA

5. Classification Contd … 5 Newer antimalarials (AAA) Artesunate Artemether  Atovoquone Cinchona alkaloids ( qqcc ) Quinine Quinidine Cinchonine Cinchonidine 4-aminoquinolines (CHMA) Chloroquine Hydroxychloroquine Mefloquine Amodiaquine

6. Classification Contd … 6 8- aminoquinolines ( ppp ) Primaquine P amaquine P e n t aquine 9-aminoacridines (QA) Quinacrine Acriquine

7. Cinchona alkaloids 7 Eg. Quinine, Quinidine, Cinchonine, Cinchonidine. Th e al k alo i d s a r e deri v a ti v es o f 4-quinoline methanol be aring a substituted quinuclidine ring system

8. SAR of Cinchona alkaloids 8 All four of the cinchona alkaloids are active antimalarials. Thus the 6- OCH 3 group is not essential for activity . 2. Quinoline methanol portion becomes important in synthetic drugs.

9. 3. All the alkaloids having same configuration at R1 & R2 are diastereoisomers , differing in configuration at 3 rd & 4 th chiral centers (C-8 and C-9)

10. SAR of Cinchona alkaloids 10 4. Although all four alkaloids show antimalarial activity, their C-9 epimers (i.e. having either 8R:9R or 8S:9S configurations) are inactive . Any modification of the 2˚ alcohol at C-9, through oxidation, esterification and similar processes diminishes activity . The quinuclidine portion is not essential for activity; however, the tertiary (3˚) alkyl amine attached to C-9 is important. This forms the basis for the design of synthetic antimalarials.

11. Cinchona alkaloids contd… 11 Metabolism: - Quinine is metabolized in the liver to the 2’ – hydroxyl (carbostyril) derivative, followed by additional hydroxylation on the quinuclidine ring to provide the 2,2’-dihydroxy derivative as the major metabolite. This metabolite has low antimalarial activity and is rapidly excreted. Excretion is mainly in the urine.

12. Cinchona alkaloids contd… 12 Effects: - The cinchona alkaloids act on the erythrocytic merozoites . They do not effect a radical cure but decrease symptoms. Quinine is use d in t r e a ting s o me f orm s o f mal a r ia, in which resistance to other agents has developed. Als o , cin c h o n a al k aloids a r e a n ti p y r etic b y the action o n c e n t r al temperature regulating mechanism causing peripheral vasodilation

13. Cinchona alkaloids contd… 13 Side effects: - Side effects include – skin allergies, deafness, vertigo (giddiness - dizziness) and slight mental depression. Quinine passes the fetal barrier and affects the vision of the new born. Advantages: - Quinine is the drug of choice only for chloroquine resistant P. falciparum. The resistance to quinine has not developed as readily as it has to the synthetic drugs.

14. Quinoline analogues - 4-aminoquinolines 14 C h l o ro q u i ne Amo d i a q u i n e Mefloquine © Ramaiah University of Applied Sciences H y dr o x y c h l o r o q u i ne

15. SAR of 4-aminoquinolones 15  Substitution of a methyl group on C-8 causes a complete loss of activity. The 3˚ amine is important for activity Side chain length (4-carbon)& 7-chloro-group are optimal for activity. Substitution of –OH gp on one of the ethyl group on the 3˚ amine reduces toxicity and increase the plasma concentrations(more effective)- a metabolite of chloroquine (hydroxyl chloroquine). Incorporation of an aromatic ring at the 3˚ amino gp, produces a compound of reduced activity and toxicity e.g amodiaquine Incorporation of a methyl group on C-3 on the quinoline ring decreases activity e.g santoquine

16. ADME of 4-aminoquinolones 17 Absorption, Distribution and excretion : Chlo r oquin e is a b s o rb e d r e a dil y f r o m the G . I , T , bu t am o diaquine gives lower plasma levels than others in the group. Peak plasma concentrations are reached in 1 to 3 hrs, with blood levels falling off rapidly after administration is stopped. About half the drug in the plasma is protein bound. These drugs concentrate in the liver, spleen, heart, kidney & brain. Thes e c omp o und s a r e e x c r e t ed r apidly with mo s t o f the unmetabolized drug being accounted for in the urine.

17. 4-aminoquinolones- uses & toxicity 16 aminoquinolines are used. Uses: - These drugs are active against the erythrocytic forms of all malarial parasites leading to clinical cure. They do not prevent the disease and they are not active against the liver infecting forms. They are also used in the treatment of extra-intestinal amebiasis. Toxicity: - The toxicity of 4-amino quinolone is quite low. The side effects include nausea, vomiting, anorexia, abdominal cramps, diarrhea, headache, dizziness, pruritus and urticaria Long-term administration in high doses may have serious effects on the eyes. Patients with liver diseases particularly should be watched when 4-

18. 8-aminoquinolines 17 8- aminoquinolines, unli k e 4- a minoquinoline s , a r e acti v e a g ain s t the pre- or exo-erythrocytic forms of the malarial parasite. 8-aminoquinolines are reserved for prophylactic purposes and for the p r oductio n o f r adi c al cu r e in i n f e c tions du e t o P . vi v a x and P . mal a riae SAR: - The 6-methoxy group is essential for activity side chain carbon length can vary from 4 to 6 carbons The extent of substitution of the amino is not as critical and the drug of choice, Primaquine, is a primary amine.

19. 8-aminoquinolines 20 Primaquine P ama quine P e n t aquine

20. 8-aminoquinolines-ADME 21 The 8-aminoquinolines are absorbed rapidly from the G. I .tract. Peak plasma concentrations are reached within 2 hours after ingestion after which the drug rapidly disappears from the blood. The drugs are localized mainly in the liver, lung, brain, heart and muscle tissue. Metabolic changes are produced in the drug very rapidly and on excretion, metabolic products account for nearly all of the drug. The antiplasmodial and the toxic properties of these drugs are produced by metabolic transformation products.

21. 8-aminoquinolines contd… 22 Toxicity: - Th e t o xi c e f f e c ts a r e p rin c ipal l y in the CN S a n d the h e m a t op o iet i c system (system pertaining to the formation of blood cells). Other side effects are anorexia, abdominal pain, vomiting and cyanosis ( a dark bluish colaration of skin and mucous membrane due to deficient oxygenation o f the blo o d in the tissues ), hemolytic anemia leukopenia ( abnormal de c r ea s e in W B C < 5000 / c u .mm ) and methem o g l obinemi a ( c o ndit i on in which more than 1% of hemoglobin is blood is oxidized to ferric form Fe +++ ) U s e s : - Pr i maquine is use d mainly t o p r e v e n t r el a p se s d u e t o e x o - erythrocytic forms of the parasites.

22. 9 -Amino a crid i nes 23 Act as schizonticides but are inferior to the 4-aminoquinolines Quinacrine hydrochloride (Mepacrine HCl) 6-chloro-9[{4-(diethylamino)-1-methylbutyl}amino]-2-methoxy acridine dihydrochloride.

23. 9 -Amino a crid i nes 24 Toxicity: - Extremely toxic - largely replaced by the 4-aminoquinolines The toxicity involves the CNS, blood and fatal drug reactions. The toxic effects include-convulsions, psychotomimetic (mental disturbances) reactions, aplastic anemia [decreased formation of erythrocytes and hemoglobin from aplastic(defective) bone marrow] and exfoliate (scabial) dermatitis A side effect of therapy is yellow pigmentation of the skin and yellow color in the urine.

24. Summary Classification of Antimalarials Structural Activity Relationship, pharmacokinetics, pharmacological effects and side effects of the following: C inchona alkalois 8aminoquinolines 4- aminoquinolines 9- acridines 25