Classifications and Synthesis of Chemotherapeutic Drugs

1. PHARMAWISDOM MEDICINAL CHEMISTRY 1 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD SULFONAMIDES German bacteriologist and pathologist who was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery (announced in 1932) of the antibacterial effects of Prontosil, the first of the sulfonamide drugs. They act as antimicrobial agents by inhibiting bacterial growth and activity and commonly called sulfa drugs. Chemically, it is a molecule containing the sulfonamido (sulfanilamide, SO2NH2) functional group attached to aniline. Structurally related to p-amino benzoic acid (PABA). This group is also present in other non-antibacterial compounds like -Sulphonureas -Benzothiazids -Furosemide -Acetazolamide MOA of SULFONAMIDE:

2. PHARMAWISDOM MEDICINAL CHEMISTRY 2 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD CLASSIFICATION: Orally absorbable agents Short acting (6-9hrs.)- Sulfadiazine Sulfacytine Sulfamethizole Sulfisoxazole Intermediate acting (10-12hrs.)- Sulfamethaxazole Sulfamoxole Long acting (7days)- Sulfadoxine Sulfamethopyrazine Orally non absorbable agents Sulfasalazine Olsalazine Topical agents Silver sulfadiazine Sulfacetamide Mafenide Some Important Structures: N H NS O O H2N Sulphapyridine N H N S O O N N COOH OH Sulfasalazine N N H NS O O H2N Sulfadiazine H NS O O H2N Sulfamethoxazole N O CH3 H NS O O H2N Sulfisoxazole O N CH3H3C

3. PHARMAWISDOM MEDICINAL CHEMISTRY 3 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD SAR of SULFONAMIDES SH2N O O NH R 4 3 2 1 p-Amino group Aromatic ring Sulfanilamide group N1 -Substitution group The amino & Sulphonyl groups on the benzene ring are essential & should be in 1,4- position Replacement of Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolish activity. Exchange of the -SO2NH group by –CO-NH reduce the activity. Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent compounds. N1 –Di substitution in general leads to inactive. GENERAL SYNTHASIS OF SULFONAMIDE NHCOCH3 4-acetamidobenzene - sulfonyl chloride Benzene Nitrobenzene NO2 NH2 NHCOCH3 SO2Cl NHCOCH3 SO2NH2 NH2 SO2NH2 Aniline Acetanilide 4-acetamidobenzene - sulfonamide Sulfonamide HNO3 H2SO4 Sn/HCl (CH3CO)2O CH3COOH ClSO3H NH3 H2O/HCl

4. PHARMAWISDOM MEDICINAL CHEMISTRY 4 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD SULPHADIAZINE NHCOCH3 SO2Cl NHCOCH3 SO2NH N N NH2 SO2NH N N H2O/H+ Sulphadiazine 2-amino pyridine N N H2N 4-acetamidobenzene - 1-sulfonyl chloride Hydrolysis SULFASALAZINE N H N S O O NH2 Sulphapyridine N H N S O O N N+ Cl- OH COOH N H N S O O N N COOH OH NaNO2/HCl Diazotisation Diazonium salt Salicyclic acid Coupling Sulfasalazine

5. PHARMAWISDOM MEDICINAL CHEMISTRY 5 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD TRIMETHOPRIM CH2OHH3CO H3CO H3CO H2 CH3CO H3CO H3CO H2N C NH NH2 Guanidine 3,4,5-Trimethoxy benzaldehyde H2C C C N N malononitrile C HC N NH2 H2 CH3CO H3CO H3CO N N NH2 H2N NH3 Trimethoprim

6. PHARMAWISDOM MEDICINAL CHEMISTRY 6 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTIVIRAL DRUGS Antiviral drugs are a class of medication used specifically for treating viral infections. CLASSIFICATION Based on their chemical structure 1. Purine Analogs: Acyclovir Vidarabin (Herpes) Zidovudine (HIV) 2. Pyrimidine Analogs Iodoxuridine Trifluridine (herpes) 3. Thio-semi carbazone Methisazone 4. Adamantine amines Amantadine Rimantadine ACYCLOVIR N N OH H2N C6H5COOCH2CH2OCH2Cl -HCl NaOH/H2O/H -C6H5COOH 2-amino-6-hydroxy purine N H N N N OH H2N N N H2C O CH2 CH2OCC6H5 O N N OH H2N N N H2C O CH2 CH2HOAcyclovir

7. PHARMAWISDOM MEDICINAL CHEMISTRY 7 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ZIDOVUDINE N HN O CH3 O O CH2OH OH N HN O CH3 O O CH2OH OSO2CH3 N HN O CH3 O O CH2OH N3 Zidovudine LiN3 DMF (Dimethyl formide) CH3SO2Cl -HCl

8. PHARMAWISDOM MEDICINAL CHEMISTRY 8 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTIFUNGAL DRUGS CLASSIFICATION: Based on chemical structure Polyenes(antibiotics): Amphotericin-B Azoles  Triazoles: fluconazole, itraconazole  Imidazole’s: clotrimazole, ketoconazole Fluorinated pyrimidine derivatives: 5-flurocytosine Acid and their salts: benzoic acid, salicylic acid. Natural products: griseofulvin FLUCONAZOLE F F C O CH2CH2Cl 2,4-difluorobenzyl ethalene chloride N N H N -HCl (1,2,4-Triazole) F F C O CH2CH2 formation alkoxide F F C H2C H2C O N N N H (1,2,4-Triazole) F F C OH H2 C N N N N C H2 Fluconazole N N N N N N N N

9. PHARMAWISDOM MEDICINAL CHEMISTRY 9 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTITUBERCULAR DRUGS CLASSIFICATION: Based on chemical moiety Salicylic acid derivatives Para amino salicylic acid Pyridine derivatives Isonicotinic acid hydrazide Ethionamide Pyrazine derivatives Pyrazinamide Ethylene Di-amino Butanol derivatives Ethambutol Antibiotics Streptomycin Cycloserine Rifampicin Kanamycin

10. PHARMAWISDOM MEDICINAL CHEMISTRY 10 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ISONIAZID N CH3 Oxidation 4-methyl pyridine N C OHO N C NHNH2O Isoniazide H2N NH2 Hydrazine -H2O ETHAMBUTOL CH3CH2CH NO2 CH2OH Reduction CH3CH2CH NH2 CH2OH 2-Nitro-1-butanol 2-amino butanol CH3CH2CH NH2 CH2OH (2 moles) ClCH2CH2Cl ethylene dichloride -2HCl CH3CH2CH H N CH2OH H2 C Ethambutol H2 C CHCH2CH3 CH2OH

11. PHARMAWISDOM MEDICINAL CHEMISTRY 11 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTILEPROSY DRUGS CLASSIFICATION: SULFONES Dapsone Thiosemi carbazones Amithiazone Phenazines Clofazimine Antibiotics Rifampicin (rifampin) DAPSONE 2 H2SO4 Condensation S O O S O O O2N NO2 HNO3/H2SO4 Nitration 4-4'-dinitrophenyl sulfone Sn/HCl Reduction S O O H2N NH2 Benzene (2 Moles) DAPSONE

12. PHARMAWISDOM MEDICINAL CHEMISTRY 12 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD CLOFAZIMINE NH NH2 Cl 4-Chlorophenyl-O-Phenylenediamine + NH2 N H Cl N N H Cl NH2 + Cl- N H N N H Cl NCH(CH3)2 FeCl3 Isopropyl amine NH2CH(CH3)2 Clofazimine

13. PHARMAWISDOM MEDICINAL CHEMISTRY 13 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTIAMEBIC DRUGS CLASSIFICATION: Based on chemical moiety Alkaloids E.g. emetine Nitroimidazoles E.g. metronidazole, tinidazole 8-hydroxy quinolones E.g. iodoquinol, chloroquine Antibiotics E.g. Bacitracin, oxytetracylin Miscellaneous E.g.diloxanide furoate METRANIDAZOLE H2N CH2CH2 1,2-diamino ethane CH3CN / Zn Catalytic hydrogination N N H CH3 2-methyl-imidazole HNO3/H2 N N H CH3O2N ClCH2CH2OH reflux 2-chloroethanol 2-methyl-5-nitro imidazole N N CH3O2N CH2CH2OH Metrandazole NH2

14. PHARMAWISDOM MEDICINAL CHEMISTRY 14 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD DILOXANIDE FUROATE NHCH3 OH + OHC C Cl Cl Cl + NaCN N OH H3C CCl O N O H3C CCHCl2 O Diloxanide furoate N-methyl amine phenol O C Cl O C O O NaOH Furoyl NaOH

15. PHARMAWISDOM MEDICINAL CHEMISTRY 15 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTIHELMINTHIC DRUGS CLASSIFICATION: Chlorinated derivatives Tetrachloro ethane Benzimidazole derivatives Mebendazole Albendazole Thibendazole Piperzine derivatives Diethyl carbamazine Heterocyclic derivatives Pyrantal pamoate Amides Niclosamide Natural products Avermectins Nilbemycin DIETHYL CARBAMAZINE HN NH + Cl C O N C2H5 C2H5 Piperzine diethyl carbamoyl chloride HN N CH3Cl Chloromethane Diethyl carbamazine C O N C2H5 C2H5 N N C O N C2H5 C2H5 H3C -HCl -HCl

16. PHARMAWISDOM MEDICINAL CHEMISTRY 16 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ALBENDAZOLE H N NO2HS C O CH3 + 2-nitro-4-mercapto acetanilide BrCH2CH2CH3 -HBr H N NO2H3CH2CH2CS C O CH3 Red/hydrolysis SnCl2 NH2 NH2H3CH2CH2CS Methyl urea H3CH2CH2CS Acylation CH3COOH Albendazole n-propyl bromide N H N NH2 H3CH2CH2CS N H N N H C CH3 O N H O H2N CH3 -CH3NH2

17. PHARMAWISDOM MEDICINAL CHEMISTRY 17 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD PYRANTEL PAMOATE N N CH3 S H HOOC OH H2 C HO COOH Pyrantel pamoate(pamoic acid) pyrantel pamoate S CHO + CN H2 C COOH Thiophene-2- carboxaldehyde cyano acetic acid knoevenagel reaction S C H CHCN CH3OH/HCl S C H CHC NH O NH2CH2CHCHNHCH 2 N-methyl propylene 1,3-diamine S C H C H N N CH3 Pyrantel

18. PHARMAWISDOM MEDICINAL CHEMISTRY 18 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTIMALARIAL DRUGS CLASSIFICATION: Based on their chemical moiety Cinchona alkaloids Quinine Cinchonine 4-amino quinolines Chloroquine Amodiaquine Hydroxychloroquine 8-amion quinolines Primaquine Pamaquine Tafenoquine Quinoline Methanol Mefloquine 9-amino acridines Quinacrine Acridine 2,4-diamino pyrimidines Pyrimethamine Trimethoprim Biguanides Proguanil Chlorproguanil Sulphonamides Sulfadoxine Sulfamethoxazole Tetracyclines Tertracycline Doxycycline Newer drugs(Sesqui Terpene Lactones) Artemisinin Artesunate Artemether Arteether

19. PHARMAWISDOM MEDICINAL CHEMISTRY 19 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD CHLOROQUINE N Cl Cl 4,7-dichloroquinoline + CH3CH(CH2)3N NH2 C2H5 C2H5 Phenol condensation N NHCH(CH2)3N Cl CH3 C2H5 C2H54-amino-1-diethylamino pentane Chloroquine PRIMAQUINE N H3CO NO2 Reduction Sn/HCl BrCH(CH2)3Br CH3 N H3CO NHCH(CH2)3Br CH3 NH3 N H3CO NHCH(CH2)3NH2 CH3 6-methoxy-8-nitroquinoline N H3CO NH2 8-amino-6-methoxy quinoline Primaquine 1,4-dibromopentane

20. PHARMAWISDOM MEDICINAL CHEMISTRY 20 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD PYRIMETHAMINE CH2Cl Cl KCN CH2CN Cl CH3CH2COC2H5 O C Cl C C2H5 CN OH HC Cl C C2H5 CN O (Enol form)(Keto form) CH3Cl C C C2H5 CN OCH3 H2N C NH2 NH Guanide N N H2N C2H5 NH2Cl Pyrimethamine Cl 1-chloro-4- (chloromethyl) benzene Ethyl propionate P h a r m a w i s d o m . b l o g s p o t . i n NORFLAXACIN CIPROFLOXACIN HN N F COOH CH3 O HN N F N COOH O

21. PHARMAWISDOM MEDICINAL CHEMISTRY 21 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD ANTINEOPLASTIC AGENTS (ANTI CANCER DRUGS) CLASSIFICATION: Based on chemical moiety Alkylating agents Nitrogen mustards Chlorambucil Cyclophosphamide Melphalan Mechlorethamine Alkyl sulphonates Busulfan Aziridines Thio-TEPA Benzo-TEPA Nitrosovrea Carmustine Lomustine Semustine Triazenes (Methyl Hydrazines) Procarbazine Dacarbazine Anti-metabolites Folate analogues Methotrexate Purine analogues 6-mercaptopurine 6-thioguanine Pyrimidine analogues 5-fluorouracil Floxuridine Cytarabine Natural products Vinca alkaloids Vincristine Vinblastine

22. PHARMAWISDOM MEDICINAL CHEMISTRY 22 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD Antibiotics Actinomycin-D Bleomycin Mitomycin Some Structures of ANTI-CANCER DRUGS CH2CH2CH2COOHN ClH2CH2C ClH2CH2C Chlorambucil CH3SO2O(CH2)4OSO2CH3 Buslulfan ClCH2CH2N C NHCH2CH2Cl O N O Carmustine P S NN N Thio-TEPA C H2 C H N H NH3C O NH CH CH3 CH3 Procarbazine N N SH N H N Mercaptopurine HN N H F O O 5-Fluoro uracil N CH3 C O H N CH COOH CH2 CH2 COOH H2 C N N N N NH2 H2N Methotrexate

23. PHARMAWISDOM MEDICINAL CHEMISTRY 23 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD CHLORAMBUCIL CH2CH2CH2COOH Conc. HNO3 CH2CH2CH2COOHO2N Pd/SOCl2 O CH2CH2CH2COOHN ClH2CH2C ClH2CH2C 4-Phenyl butyric acid CH2CH2CH2COOHH2N 4-(4-aminophenyl)butanoic acid 4-(4-nitrophenyl)butanoic acid CH2CH2CH2COOHN HOH2CH2C HOH2CH2C Chlorambucil POCl3 Ethylene Oxide BUSULFAN CH3SO2Cl Methane sulfonyl chloride (2moles) + OH(CH2)4OH 1,4-Butanediol CH3SO2O(CH2)4OSO2CH3 Buslulfan Pyridine - 2HCl

24. PHARMAWISDOM MEDICINAL CHEMISTRY 24 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD CARMUSTINE NH + COCl2 Aziridine (2moles) N C N O 2HCl ClCH2CH2NH C NHCH2CH2Cl O 1,3-bis-2-chloroethyl urea NaNO2 HCOOH ClCH2CH2N C NHCH2CH2Cl O N O Carmustine Phosgene -2HCl di(aziridin-1-yl)methanone 5-FLUROURACIL N H HN O O Uracil CF3OF Fluoroxy trifluro methane HN N H F O O 5-Fluoro uracil Fluorination

25. PHARMAWISDOM MEDICINAL CHEMISTRY 25 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD 6-MERCAPTOPURINE HN N O N H N Hypoxanthine POCl3 N N SCN N H NN N Cl N H N Pyridine 6-chloro purine NaSCN -NaCl N N SH N H N Mercaptopurine H2O METHOTREAXATE (AMETHOPTERIN) N N NH2 NH2 NH2H2N 2,4,5,6-Tetra amino pyrimidine + BrCH2CHCHO Br 2,3-dibromo propionaldehyde + HN CH3 C O H N CH COOH CH2 CH2 COOHMethyl amino benzoyl glutamate lime water NaOH CH3COOH N CH3 C O H N CH COOH CH2 CH2 COOH H2 C N N N N NH2 H2N Cyclization Dehydration -2HBr/H2O Methotrexate

26. PHARMAWISDOM MEDICINAL CHEMISTRY 26 S.SEETARAMSWAMY, Asst.Professor, CBCP, HYDERABAD VINCA ALKALOIDS N H N OH C2H5 H3COOC N H3CO N H HO OCOCH3 COOCH3 C2H5H R R = CHO - Vincristine R = CH3 - Vinblastine

Classifications and Synthesis of Chemotherapeutic Drugs

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Classifications and Synthesis of Chemotherapeutic Drugs

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Classifications and Synthesis of Chemotherapeutic Drugs