Quinolines- Antimalarial drugs.pptx

General introduction about quinoline anti-malarial drugs, QSAR, examples, Applications and side effects.

1. Quinolines- Antimalarial drugs By- Ayushi Dogne

2. Content- Introduction What are quinolines? Structure Classification of quinolines 4- Aminoquinoline: SAR, examples 8-Aminoquinoline: SAR, examples Cinchona Alkaloids Quinoline methanol 3/1/20XX 2

3. Introduction Sample footer text 3/1/20XX 3 A ntimalarial drugs or medications are the drugs and medicines which are formulated and designed to prevent, treat and cure the symptoms of malaria. Malaria is a disease which is spread by a genus of mosquitoes called Anopheles mosquito. The mosquito infects the blood by biting or injecting its parasitic saliva into the blood. In humans malaria is caused by malarial parasites: Plasmodium falciparum Plasmodium vivax Plasmodium malariae [Quartan malaria]

4. What are quinolines? Sample footer text 3/1/20XX 4 Quinoline is a heterocyclic aromatic organic compound with the chemical formula C 9 H 7 N. It is a colorless hygroscopic liquid with a strong odor. If quinolines are exposed to light, become yellow and later brown. Quinoline is slightly soluble in cold water but dissolves readily in hot water and most organic solvent. Quinoline containing antimalarial drugs, such as chloroquine, quinine and mefloquine, are mainstays of chemotherapy against malaria. Quinoline ring

5. Structure- All carbons and nitrogen are sp 2 hybridized. The lone pair of electrons of nitrogen remains in sp 2 hybridization orbitals same as in case of pyridine and do not take part in formation of delocalized π molecular orbital. Total 10  π -electrons [ 9 π -electrons of carbon and 1 π -electron of nitrogen] are delocalized in  π molecular orbitals. Quinoline satisfies Huckel’s Rule i.e. 4n+2 π , so it is aromatic in nature. Resonance in quinoline- Sample footer text 3/1/20XX 5

6. Classification of Quinolines- 4-Aminoquinolines : Chloroquine, Amodiaquine, Hydroxychloroquine 8-Aminoquinolines : Primaquine phosphate, Pamaquine Cinchona Alkaloid : Quinine sulphate, Quinidine Quinoline methanol : Mefloquine Sample footer text 3/1/20XX 6

7. 4-Aminoquinolines 4-Aminoquinoline is a form of aminoquinoline with amino group at the 4 th position of the quinoline. A variety of derivatives of 4-aminoquinoline are antimalarial agents useful in treating erythrocytic plasmodial infections. Chloroquine was one of the drugs successfully developed. The drug was first used during the 1950’s. Sample footer text 3/1/20XX 7

8. SAR of 4-Aminoquinolines- 8 Quinoline ring- It is essential for activity of drug, and is more active than acridine. At 4 th position substituted amino group is essential for its activity. It is substituted with dialkylaminoalkyl side chain which provide maximum activity. Aromatic ring on sidechain or hydroxy group in nitrogen reduces it’s activity and toxicity too. Generally at 3 rd position hydrogens are substituted, if at place of hydrogen methyl group is substituted, the antimalarial activity og drug would get decreased. At 7 th position Chloro group is essential for its activity, if it gets replaced by any other group then the activity of compound gets reduced. At 8 th position if hydrogen group is relaced by methyl or other group then it will abolish the activity i.e. complete loss of activity.

9. A. Position of c-4 & sidechain at amino group: Amino group at 4 th position is essential. This amino group at C-4 contains dialkylaminoalkyl side chain for maximum activity. This dialkylaminoalkyl sidechain has 2-5 carbon atoms between two nitrogen atoms. 4-Diethylaminomethyl butylamino side chain is most suitable at 4 th position. E.g.- Chloroquine. Tertiary amino group in the side chain is important for activity. The substitution of hydroxy group on one of the ethyl groups Chloroquine on the tertiary amine reduces toxicity. E.g.- Hydroxychloroquine. Introduction of aromatic ring in side chain produces compound with reduced toxicity & activity. E.g.- Amodiaquine Amodiaquine Sample footer text 3/1/20XX 9

10. B. Other positions on Quinoline rings- Chloro group at 7 th position in necessary for antimalarial activity. E.g.- Chloroquine Introduction of methyl group at 3 rd position reduce the activity. Quinoline ring is more active than acridine for same side chain. E.g.- Quinoline containing chloroquine is more active than Quinacrine {acridine}. If we substitute amino group at 8 th position in place of 4 th position it will produce another class of potent antimalarial drugs namely 8-Amino Quinolines . Sample footer text 3/1/20XX 10

11. Chloroquine- Chloroquine is an antiparasitic medicine, used for the prevention and treatment of malaria. It works by killing the malaria causing parasite and stops the infection from spreading. Chloroquine is also occasionally used for  amebiasis   that is occurring outside the   intestines ,  rheumatoid arthri tis , and  lupus erythematosu s. Use to treat: Malaria Brand Names : Larigo, Emquine etc. Drug Class : Antimalarial- Aminoquinolines (4-Aminoquinoline derivative) Chloroquine may be unsafe to use during pregnancy. However, the benefits from use in pregnant women may be acceptable despite the risk. Please consult your doctor. Chloroquine is safe to use during lactation . Sample footer text 3/1/20XX 11

12. Side effects of Chloroquine- Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhoea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems. Unwanted/uncontrolled movements (including tongue and face twitching)  Deafness or  tinnitus. Mental/mood changes (such as confusion, personality changes, unusual thoughts/behaviour, depression, feeling being watched, hallucinating). Signs of serious infection (such as high fever, severe chills, persistent sore throat). Itchiness , skin colour changes, hair loss, and skin rashes. Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. Chloroquine induced retinopathy . Sample footer text 3/1/20XX 12

13. 8-Aminoquinolines - 8-Aminoquinoline is the 8-amino derivative of quinoline. It is structurally analogous to 8-hydroxyquinoline. The two nitrogen atoms are ideally situated to form complexes with metal ions. Derivatives of 8-aminoquinoline are effective directing groups in organic synthesis . Sample footer text 3/1/20XX 13

14. SAR of 8-Aminoquinoline- Substitution of methyl at 4 th position gives active compound. E.g.- 4-Methylprimaquine. Substitution of methyl group at 2 nd , 3 rd and 5 th position reduces the activity and toxicity of compound. At 6 th position methoxy group is essential for the activity. E.g.- Primaquine, Pamaquine. Amino group at 8 th position should have: Side chain which would be as same as 4-aminoquinoline. Primaquine Terminal amino group would be primary [Primaquine] , secondary [ Pentaquine ] and tertiary [Pamaquine]. At 5 th and 6 th position dihydroxy substitution may produce active compounds but they would highly toxic in nature. Sample footer text 3/1/20XX 14

15. Primaquine- Primaquine is a medicine which is used to treat and prevent malaria and to treat Pneumocystis pneumonea . It is used for malaria due to P. vivax and P. ovale . It is an alternative treatment for Pneumocystis pneumonia together with clindamycin. It is taken through oral route. Mechanism of action - Primaquine is lethal to  P. vivax  and  P. ovale  in the liver stage, and also to  P. vivax  in the blood stage through its ability to do oxidative damage to the cell. Sample footer text 3/1/20XX 15

16. Adverse effects of primaquine- Common side effects of primaquine administration include nausea, vomiting, and stomach cramps. In person with cytochrome B5 reductase deficiency, primaquine causes methemoglobinemia, a condition in which the blood carries less oxygen than it usually carries. Overdosing can reduce number of blood cells. Person with glucose-6-phosphate dehydrogenase deficiency may devlop hemolytic anemia from primaquine. Sample footer text 3/1/20XX 16

17. Pamaquine- Pamaquine  is an  8-aminoquinoline  drug formerly used for the treatment of  malaria . It is closely related to  primaquine . Uses: Pamaquine is effective against the hypnozoites of the relapsing malarias ( P. viva  and  P. ovale ); and unlike primaquine, it is also very effective against the erythrocytic stages of all four human malarias. Pama quine is more toxic than primaquine therefore, pamaquine is no longer routinely used. Adverse effect: Like primaquine, pamaquine causes haemolytic anaemia in patients with G6PD deficiency. Sample footer text 3/1/20XX 17

18. Chinchona alkaloids Quinine: In 1820, scientist name Pelletier & Caventou isolated quinine from cinchona bark. It is l-isomer of alkaloid obtained from cinchona bark. It is an effective erythrocytic schizonticide as suppressive and used to prevent or terminate attacks of vivax, ovale , malariae sensitive falciparum. It is moderately effective against hepatic form i.e. exoerythrocyte and gametocytes. Sample footer text 3/1/20XX 18

19. Mechanism of action- Like chloroquine it is a weak base and acts by inhibiting polymerization of heme to hemozoin. Free heme or heme -quinine complex damages parasite’s membrane and kills it. Pharmacokinetics- It get well absorbed from GI tract, even in patients with diarrhoea. It get metabolized in liver and excrete out through urine. Adverse effect- Higher dose symptom includes nausea, vomiting, tinnitus, vertigo, headache, difficulty in hearing and diarrhoea. If given through rapid I.V. injection can cause hypotension and cardiac arrythmia. It can also cause profused hypoglycemia . In pregnancy, it can use abortion by stimulating myometrium and premature labor by stimulating uterus. Sample footer text 3/1/20XX 19

20. Quinoline methanol- Mefloquine- Quinoline methanol derivatives developed to deal with chloroquine resistant malaria. Rapidly acting erythrocytic schizonticide, slower than chloroquine and quinine. Effective against chloroquine sensitive and resistant plasmodium. Its mechanism of action is similar to chloroquine. Pharmacokinetics- Good but slow oral absorption. Shows high protein binding. Concentrated in liver, lungs, intestine. Extensive metabolism in liver, primarily secreted in bile and undergoes enterohepatic circulation. Half life= 2-3 weeks. Sample footer text 3/1/20XX 20

21. Adverse effects- Bitter taste, nausea, vomiting, abdominal pain, diarrhoea. Causes neuropsychiatric disturbance. Bradycardia, sinus arrythmia. Teratogenicity. Allergic skin reactions, hepatitis, blood dyscrasias. Thank you Sample footer text 3/1/20XX 21