1. MEDICINAL CHEMISTRY OF AZOLE & BARBITURATES 1

2. AZOLE : An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of either nitrogen, sulphur or oxygen. A majority of compounds produced by nature have heterocyclic rings as part of their structures. Many heterocyclic rings are found as key components in biological systems. 2

3. Classification: 1 nitrogen (and no other heteroatom) Pyrrole: 2 or more nitrogen atoms Pyrazole Imidazole Triazole Tetrazole 1 nitrogen atom and 1 oxygen atom Oxazole Isoxazole 1 nitrogen atom and 1 sulphur atom Thiazole Isothiazole 3 Pyrrole Triazole Tetrazole

4. Classification according to pharmacological actions Adrenergic agents : Clonidine, Phentolamine, Tolazoline, Cholinergic agents : Pilocarpine HCl Sulphonamides: Sulphamethizole, Sulfisoxazole, Sulphamethoxazole. Cephalosporins: Cefazoline sodium, Cefonacid sodium, Ceforanide, Cefoperazone, Cefmetazole, Cefotetan sodium, Cefixime, Cefotaxime sodium, Diuretics : Muzolimine, Acetazolamide, Methazolamide Cardiovascular agents : Saralasin, Methimazole Antihistaminic agents: Famotidine, Cimetidine, Analgesics: Etonitazene Anti- inflammatory analgesics : Tolmetin, Phenylbutazone Steroids: Imazodan, pimobendan Amino acids : Histidine, tryptophan

5. Antiviral : Ribavirin, Ritonavir, Vidarabin, Acyclovir, Valacyclovir, Ganacyclovir, Famciclovir, Penciclovir Antineoplastic agents: Dacarbazine, Mercaptopurine Immunotherapy: Levamisole CNS depressants: Etomidate, Alprazolam, Midazolam, Triazolam Antipsychotics: Ondansetron CNS stimulants: Pentylene tetrazole, Methyl xanthines, Pemoline, Isocarboxazid, Mazindol, Trazodone HCl Vitamins: vitamin B 1, vitamin B 12.

6. IMIDAZOLE : Imidazole is an azapyrrole. First prepared in 1858. Imidazole is a 5- membered heterocyclic ring containing 2 nitrogen atoms at 1,3 positions. e.g. Metronidazole, Benznidazole, Dacarbazine, Etomidate, Midazolam, Flumenizil, Ondansetron, Pilocarpine hydrochloride, Saralasin, Methimazole, Cimetidine, Imazodan, Histidine, Histamine, Burimamide, Metiamide, Immepip, Thioperamide, Clobenpropit, 4-Methyl histamine, Carnosine, Priscol, Privine, Azamicin, Butoconazole, Clotrimazole, Econazole, Sulconazole, Oxiconazole, Ketoconazole, Miconazole, Tioconazole, Allantion etc… Imidazoline : Clonidine, Phentolamine, Tolazoline, Mazindol, Antazoline phosphate, Naphazoline, Oxymetazoline, Xylometazoline. Imidazolidine dione: Phenytoin, Ethotoin, Nitrofurantoin, Dantrolene sodium 6

7. Dacarbazine cimetidine histidine amino acid Anticancer drug antiulcer agent Etomidate Ondansetron pilocarpine CNS depressant antipsychotic cholinergic Azamycin phenytoin Antihistaminic anticonvulsant Antihypertensive

8. Midazolam Muzolimine CNS depressant diuretic

9. FUSED RING SYSTEMS INVOLVING IMIDAZOLE: BENZIMIDAZOLES: Thiabendazole Albendazole Antihelmentic Anthelmentic lansoprazole omeprazole Antiulcer drug antiulcer drug Etonitazene (analgesic)

10. Purine: Famciclovir (antiviral) acyclovir NAD anticancer drug Azathiopurine (anticancer agent) Adenosine Methyl xanthines

11. Metronidazole USP: MOA : It enters the bacteria via electron transport protein ferredoxin, it is reduced and then bind to DNA causing loss of helical structure, strand breakage and impairment of DNA function. Synthesis: 11

12. Uses: Treatment of specific protozoal infections like amoebiasis, Trichomoniasis, Giardiasis, Balantidiasis. Adverse effects: Diarrhea, Nausea, Insomnia, Ataxia, Vomiting Metabolism: It is metabolized by cytochrome P450 system. Methyl group is oxidized to hydroxy methyl group, ethanol side chain is oxidized to an acid group (-CH 2 COOH) both are active metabolites. Brand name: ALDEZOLE, METROGYL 12

13. Triazole: Triazole is a 5-membered heterocyclic ring containing three nitrogen atoms. e.g. Ribavirin, Triazolam, Alprazolam, Trazodone, Itraconazole, Fluconazole, Terconazole. 13 Ribavirin Triazolam Alprazolam Antiviral CNS depressant CNS depresasnt

14. Fluconazole: MOA: It inhibits cytochrome p450 dependent enzymes resulting in impairment of ergosterol synthesis in fungal cell membrane of the fungi. It act by inhibiting “Lanosterol – 14- α –demethylase” which is the enzyme involved in early stages of synthesis of ergosterol. Inhibits oxidative demethylation and retains excess of Lanosterol which destablishes the cell. 14

15. Uses : Treatment of Candidiasis and to control esophageal or oropharyngeal Candidiasis, Vaginal Candidiasis. It is also used to treat Cryptoccocal meningitis and Cryptococcosis in AIDS. Adverse effects: Abdominal pain, Hepatotoxicity, Flatulence, Nausea and vomiting, Diarrhea. Metabolism: Glucuronide conjugation Brand name: ADCON, ALFUCOZ 15

16. Synthesis: 16

17. Azole antifungals: Higher dose Fungicidal they are responsible for leakage of essential cellular component due to rupture/ lysis of cell membrane. Low dose Fungistatic action is due to inhibition of various enzymes involved in biochemical processes. Mechanism of action: They act by decreasing the CYP 450 membrane bound i.e. “Lanosterol – 14- α –demethylase” which is the enzyme involved in early stages of synthesis of ergosterol. Inhibits oxidative demethylation and retains excess of Lanosterol which destablishes the cell. 17

18. Clotrimazole and Miconazole- substituted imidazoles They are initially discovered and thus serve as lead molecules. Drawback : 1) They are Hepatotoxic 2) Endocrine toxic Isosteric replacement of imidazole with “1,2,4-Triazole” led to discovery of compound like Fluconazole, Itraconazole, which pocess less side effects. SAR of Azole antifungals: They are characterized by presence of a weekly basic imidazole / 1,2,4-triazole nucleus for antifungal activity. The amidine ‘N’ atom at 3 rd position of imidazole and 4 th position of triazole are responsible for decreased concentration of heme iron due to complexation decrease Fe+2 decrease cell respiration Hypoxia All azole consists of 2 or 3 bulkier substituents like phenyl/substituted phenyl group which imparts lipophilicity so as to disturb cell membrane. 18

19. Presence of non polar groups increases lipid solubility while polar groups increases aqueous solubility. e.g. Fluconazole consists of 2 triazole nuclei which is highly water soluble and can be administered by I.V route. Clotrimazole: Butoconazole: Econazole : 19

20. Sulconazole: Oxiconazole: Tioconazole: Miconazole: Ketoconazole: Itraconazole: 20

21. THIAZOLE : Thiazole is a 5 membered heterocycle containing sulphur and nitrogen at 1,3 positions respectively. Examples of drugs: cefpodoxime proxetil, ceftizoxime, cefixime, cefotaxime, ceftriaxone, ceftazidim, cefpirome, cefipime, ceftibuten, aztreonam, tigemonam, bacitracin A, ritonavir, famotidine, nizatidine, thiamine, siomycin, thiosterepton, micrococin, phleonycin, bleomycin, levamisole, sulfasomizole. 21 Aztreonam Bleomycin ( antibiotic) (monobactum) Ritonavir (antiviral) Levamisole(anthelmentic)

22. Nizatidine Treat peptic ulcer Thiabendazole anthelmentic

23. FAMOTIDINE: MOA: It acts as a competitive reversible H 2 antagonist USES: Used for duodenal ulcer, gastric ulcer. ADVERSE EFFECTS: GI discomfort, constipation, head ache, digginess METABOLISM: Deamination, Glucuronide conjugation. BRAND NAME: FALTIDIN, FAMOCID

24. SYNTHESIS: 24

25. Thiadiazole: It is a 5-membered heterocyclic ring containing 3 hetero atoms (one sulphur and two nitrogen atoms). e.g. Sulphamethizole, Cefazoline sodium, Timolol, Acetazolamide, Methazolamide. 25 Sulfamethizole cefazoline sodium Acetazolamide Antibacterial antibiotic(antibacterial) diuretic methazolamide (diuretic)

26. TIMOLOL IP: MOA: Timolol is a Beta – blocker Beta adrenergic receptors activate adenyl cyclase through G protein which leads to accumulation of cyclic-AMP dependent protein kinase which will phosphorylate the cellular proteins and produce hypertension. The beta blockers bind to receptors and block their activity and reduce hypertension. USES: Antihypertensive agent. ADVERSE EFFECTS: Fatigue, skin rash, alopecia, dry mouth, blurred vision, heart failure. 26

27. BRAND NAME: GLUCOMOL,IOTIM METABOLISM: N- dealkylation, Glucuronide conjugation. SYNTHESIS: 27

28. Oxazole and Isoxazole: Oxazole is a five membered heterocycle containing oxygen and nitrogen at first and third positions respectively. Isoxazole is a five membered heterocycle containing oxygen and nitrogen at 1, 2 positions respectively. Oxazole: Pimprinine, calcinomycin, griseoviridin, sulfamoxol, sulfaguanol Isoxazole : Sulphamethoxazole USP, Sulfisoxazole USP, isocarboxazid, oxacillin, cloxacillin, dicloxacillin, methicillin.. 28 Sulfisoxazole (antibacterial) Isocarboxazid(CNS stimulant) cloxacillin (antibiotic) antibiotic Dicloxacillin (antibiotic) Acivicin(antibiotic)

29. Sulphamethoxazole USP : MOA: 29

30. USES: 1. It is used as a antibacterial agent. 2. Cotrimoxazole contains Sulphamethoxazole and trimethoprim in 5:1 proportions to produce bactericidal and bacteriostatic action against wide range of gram positive and gram negative organisms. It is also used to treat respiratory and gastrointestinal tract infections. Adverse effects: Diarrhoea, nausea, vomiting, renal failure. Metabolism: Deamination, Glucuronide conjugation. Brand name: ANTRIMA, BACTRIM. Synthesis: 30

31. Sulfamoxol: USES: Antibacterial agent. ADVERSE EFFECTS: Hypersensitivity skin reactions, crystalluria, METABOLISM: Deamination, Glucuronide conjugation. BRAND NAME: SULFUNO SYNTHESIS: 31

32. Tetrazole: Tetrazole is a five membered heterocyclic ring containing four nitrogen atoms. Examples of drugs: Cefonacid sodium USP, ceforanide USP, cefoperazone, cefmetazole, cefotetan, pentylenetetrazol. 32 Cefonacid (antibacterial antibiotic) ceforanide (antibacterial antibiotic) Cefoperazone (antibacterial antibiotic) cefmetazole pentylenetetrazol (antibacterial antibiotic) CNS stimulant

33. CEFOTETAN: MOA: It act by inhibiting the synthesis of bacterial cell wall, resulting in cell lysis. Beta lactum antibiotics are structurally similar to D-alanyl-D- alanines(component of peptidoglycon), they are able to react with penicillin binding proteins. Cephalosporins disrupt the synthesis of peptidoglycon layers of bacterial cell wall. USES: Antibacterial antibiotic. ADVERSE EFFECTS: Nausea, vomiting, hypersensitivity reactions, irritation etc. METABOLISM: N-dealkylation, Desulphuration BRAND NAME: CEFOTAN 33

34. 34 SYNTHESIS:

35. PYRAZOLE: It is a five membered heterocycle containing 2 nitrogen atoms at 1, 2 position. Examples of drugs: Muzolimine, Orisul, antipyrine, phenylbutazone, oxyphenbutazone, sulfinpyrazone, pyrazofurin, tetrazin, metamizole. Antipyrine Orisul NSAID NSAID Bacteriostatic Oxyphenbutazone pyrazofurin butazolidine( NSAID) NSAID Antiviral

36. Phenylbutazone: MOA: Uses: Non-steroidal anti-inflammatory agent. Adverse effects: head ache, digginess, insomnia Metabolism: N-Dealkylation, Aromatic hydroxylation

37. Synthesis: 37

38. PYRROLE: It is a five membered heterocyclic compound containing one nitrogen atom. Examples of Drugs : Tolmetin, Zomepirac etc.. NSAID Chlorophyll (pigment) Cyanacobalamine (vitamine) Heamoglobin (blood)

39. FUSED RING SYSTEMS INVOLVING PYRROLE : INDOLE: PYRROLIDINE Tryptophan Ergotamine Reserpine vv amino acid antioxytocic antihypertensive Vinblastin(anticancer) pindolol (beta-bloker) Nicotine Procyclidine remoxipride (withdrawal sympoms of tobacco smokers) antihistaminic CNS depressant Phensuximide (CNSdepressant) Ethosuximide (CNS depressant) methsuximide (CNS depressant)

40. TOLMETIN: USES: Non-steroidal anti-inflammatory agent. ADVERSE EFFECTS: Insomnia, blurred vision, head ache, digginess METABOLISM: Metabolized to dicarboxylic acid (oxidation at benzylic carbon atoms) BRAND NAME: TOLECTIN

41. SYNTHESIS: 41

42. BARBITURATES

43. Barbiturates are central nervous system depressants. They produce wide spectrum of CNS depression, from mild sedation to coma, and have been used as a sedatives, hypnotics, anesthetics and anticonvulsants. Barbiturate development : In 1864 von Baeyer synthesized the first barbiturate, barbituric acid. The first hypnotic barbiturate, diethylbarbituric acid, was synthesized by Fischer and Mering in 1903. In 1932 Weese and Schapff synthesized the first rapid onset, short duration barbiturate, methylated oxybarbiturate hexobarbital. Thiopental was first administered by Waters and Lundy in 1934.

44. CLASSIFICATION

45. Chemistry of barbiturates: 1.Barbiturates are derivatives of barbituric acid which is devoid of sedative and hypnotic activities. 2.Barbituric acid is described as “ cyclic ureide of malonic acid”. Barbituric acid can be made by condensing urea with ethyl malonate in presence of sodium ethoxide 2.Clinically important hypnotic-sedative barbiturates have substitutions at Sites 1,2 and especially 5 of barbituric acid.

46. Mechanism of Action Barbiturates potentiate the effect of GABA at the GABA-A receptor. The GABA-A receptor is a ligand gated ion channel membrane receptor that allows for the flow of Cl through the membrane in neurons. GABA is the principle neurotransmitter for this receptor which upon binding causes the channel to open and creates a negative change in the transmembrane potential. This makes it an Inhibitory neurotransmitter GABA binding site Barbiturate binding site GABA

47. Barbiturates potentiate the effect of GABA by binding to the GABA-A receptor at a nearby site and increasing the chloride flow through the channel. Barbiturates also block the AMPA receptor which is sensitive to glutamate, the excitatory neurotransmitter. Glutamate performs the opposite effect from GABA restricting ion flow and increasing the transmembrane action potential of the neuron. By blocking this action Barbiturates serve to increase the duration of the receptor response to GABA and extend the depressed condition of the cell.

48. USES: Barbiturates have been used to treat insomnia but they should not be used regularly bcoz they are not effective for longer than 2 weeks. They are used to relieve nervousness or restlessness during day time. If too much of barbiturate is used it may become habit-forming. They may be used before surgery to relieve anxiety or tension. Some of them are used as anticonvulsants to control seizures (epilepsy). However they are generally been replaced by safer medicines for the treatment of insomnia, day time nervousness or tension. They are used as sedative hypnotic drug, anesthetics.

49. SAR: 1)Hypnotic activity: side chains at position-5 (especially if one of them is branched ) is essential for activity. 2)Potency and duration of action: length of side chain at position-5 influences potency and duration of action. Ex: Secobarbital and Thiamylal are slightly more potent than pentobarbital and thiopental respectively. 3)More rapid onset and short duration of action: sulphur instead of oxygen at position-2. Ex: Thiamylal and Thiopental have more rapid onset and shorter duration of action than Secobarbital and Pentobarbital respectively. 4)Increased incidence of excitatory side effects: methylation at position -1 (Methohexital). 5)Increased potency, rate of onset : increase in lipophilicity of the compound.

50. 6) Introduction of polar groups into C-5-alkyl side chain makes the compound more hydrophilic in nature (excreted). 7) Branched, cyclic, unsaturated side chain at C-5 position generally reduce the duration of action due to increased ease of metabolic conversion to a more polar inactive metabolite. 8) stereoisomerism: though their l-isomers are nearly as potent as their d-isomers, barbiturates are marketed as racemic mixtures. Side effects: hangover with drowsiness, digginess, ataxia, respiratory depression. Hypersensitivity reactions, headache, confusion, slurred speech, slowed reflexes. Metabolism: N-dealkylation, Desulphuration

51. Chemical structure of the barbiturates (Seconal) (Amytal) (Pentothal)

52. (Nembutal) (Mebaral) (Luminal) (Evipal)

53. Phenobarbitone: It occurs as sodium salt. it is hygroscopic, water soluble, bitter taste, odorless, white crystalline power. Synthesis : 1. 2. 3.

54. Amobarbitone Mephobarbital

55. REFERANCES : TEXT BOOK OF ORGANIC MEDICINAL & PHARMACEUTICAL CHEMISTRY- WILSON & GISVOLD FOYE’S PRINIPLES OF MEDICINAL CHEMISTRY FIFTH EDITION MEDICINAL CHEMISTRY- NADENDLA RAMA RAO TEXT BOOK OF MEDICINAL CHEMISTRY- S.PANDEY A TEXT BOOK OF MEDICINAL CHEMISTRY- KADAM BIOPHARMACEUTICS AND PHARMACOKINETICS D.M BRAHMANKAR SUNIL B. JAISWAL