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MEDICINAL CHEMISTRY OF AZOLE & BARBITURATES 1 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 Classification: • 1 nitrogen (and no other heteroatom) Pyrrole: N • 2 or more nitrogen atoms H Pyrrole Pyrazole 1 Imidazole 5 NH N N Triazole N2 N 4 N N H 3 Tetrazole Triazole Tetrazole • 1 nitrogen atom and 1 oxygen atom Oxazole Isoxazole • 1 nitrogen atom and 1 sulphur atom Thiazole Isothiazole 3 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 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 B1 , vitamin B12 . IMIDAZOLE : 1 2 HN N3 5 4 Imidazole is an azapyrrole. First prepared in 1858. Imidazole is a 5membered 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 Dacarbazine Anticancer drug cimetidine antiulcer agent Etomidate CNS depressant Ondansetron antipsychotic Azamycin Antihistaminic phenytoin anticonvulsant histidine amino acid pilocarpine cholinergic Antihypertensive Midazolam CNS depressant Muzolimine diuretic FUSED RING SYSTEMS INVOLVING IMIDAZOLE: BENZIMIDAZOLES: Thiabendazole Antihelmentic lansoprazole Antiulcer drug Albendazole Anthelmentic omeprazole antiulcer drug Etonitazene (analgesic) Purine: SH H N N N N Famciclovir (antiviral) acyclovir Mercaptopurine anticancer drug Azathiopurine (anticancer agent) Methyl xanthines Adenosine NAD Metronidazole USP: N N O2N CH3 CH2CH2OH 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: N N HNO3/H2SO4 Ethylene chlorhydrin N Nitration N 2-methyl imidazole CH3 O2N N N H O2N CH3 2-methyl5-nitro imidazole CH3 CH2CH2OH Metronidazole 11 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 (-CH2COOH) both are active metabolites. Brand name: ALDEZOLE, METROGYL 12 Triazole: 1 5 NH N2 4 N 3 Triazole is a 5-membered heterocyclic ring containing three nitrogen atoms. e.g. Ribavirin, Triazolam, Alprazolam, Trazodone, Itraconazole, Fluconazole, Terconazole . Ribavirin Antiviral Triazolam CNS depressant Alprazolam CNS depresasnt13 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. Squalene Squalene epoxidase Squalene epoxide Squalene epoxide cyclase HO Lanosterol Lanosterol 14alpha demethylase HO HO Ergosterol 14-demethylanosterol 14 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 Synthesis: O H2 C Cl F O H2 C C C F 1,2,4-Triazole EtOAc Cl-CH2-CH2-C-Cl F F F O N N N H2C H2C N C H2C C N N O F C H2 + N N N F H N N OH N C N N Fluconazole N Trimethyl sulfoxonium iodode F F 16 Azole antifungals: Higher dose Fungicidal Low dose Fungistatic Mechanism of action: they are responsible for leakage of essential cellular component due to rupture/ lysis of cell membrane. action is due to inhibition of various enzymes involved in biochemical processes. 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 • 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 3rd position of imidazole and 4th 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 18 membrane. • 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 : N N Cl CH2 CH2 CH2 C S H Cl Cl 19 Sulconazole: Miconazole: Oxiconazole: Tioconazole: Ketoconazole: Itraconazole: 20 THIAZOLE : Thiazole is a 5 membered heterocycle containing sulphur N and nitrogen at 1,3 positions respectively. Examples of drugs: cefpodoxime proxetil, ceftizoxime, S cefixime, cefotaxime, ceftriaxone, ceftazidim, cefpirome, cefipime, ceftibuten, aztreonam, tigemonam, bacitracin A, ritonavir, famotidine, nizatidine, thiamine, siomycin, thiosterepton, micrococin, phleonycin, bleomycin, levamisole, sulfasomizole. Aztreonam Bleomycin ( antibiotic) (monobactum) Ritonavir (antiviral) Levamisole(anthelmentic) 21 Nizatidine Treat peptic ulcer Thiabendazole anthelmentic FAMOTIDINE: MOA: It acts as a competitive reversible H2 antagonist USES: Used for duodenal ulcer, gastric ulcer. ADVERSE EFFECTS: GI discomfort, constipation, head ache, digginess METABOLISM: Deamination, Glucuronide conjugation. BRAND NAME: FALTIDIN, FAMOCID SYNTHESIS: COOC2H5 + NH2CSNH2 N Br-CH2COCOOC2H5 Thiourea S H2N 1.Ac2O N C CH2 2.Li(C2H5)3H CH2S CN CH2 N CH2OH N HS-CH2-CH2 O O S H3C S CHN H3C CHN CH3OH/HCl NH N N H2C S H2N S C-OCH3 S CH2 S CH2 CH2 H2C CH3S-C-NH2 HN H2N CH2 C C-OCH3 NH NH NH 30-350C NH2SO2NH2/CH3OH Famotidine 24 Thiadiazole: 5 S1 N2 4 N 3 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. Sulfamethizole Antibacterial cefazoline sodium antibiotic(antibacterial) Acetazolamide diuretic 25 methazolamide (diuretic) 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 BRAND NAME: GLUCOMOL,IOTIM METABOLISM: N- dealkylation, Glucuronide conjugation. SYNTHESIS: O Cl OH Cl O ClCH2CH N CH2 CH3 Epichlorhydrin N OCH2CH N N S S 4-Chloro-3-hydroxy thiazole H3C Cl OH H3C CH H3C CHNH2CH2CH(OH)CH2NH N H3C N S O OCH2CH(OH)CH2NHC NH O CH3 CH3 CH3 N N N S Timolol 27 Oxazole and Isoxazole: Oxazole is a five membered heterocycle containing oxygen and nitrogen at first and third positions respectively. N Isoxazole is a five membered heterocycle containing oxygen and O nitrogen at 1, 2 positions respectively. N O Oxazole: Pimprinine, calcinomycin, griseoviridin, sulfamoxol, sulfaguanol Isoxazole : Sulphamethoxazole USP, Sulfisoxazole USP, isocarboxazid, oxacillin, cloxacillin, dicloxacillin, methicillin. . Sulfisoxazole (antibacterial) Isocarboxazid(CNS stimulant) cloxacillin (antibiotic) 28 antibiotic Dicloxacillin (antibiotic) Acivicin(antibiotic) Sulphamethoxazole USP : MOA: NH2 PTERIDINE PABA NH2 Dihydopteroate synthetase SULPHONAMIDES COOH P-Amino benzoic acid SO2NH2 Dihydropteroic acid Sulphonamide Folic acid 29 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: NHCOCH NHCOCH 3 3 O N NH2 + Condensation H3C SO2Cl SO2NH NH2 N O CH3 Alkaline hydrolysis SO2NH N O CH3 30 Sulfamoxol: CH3 N H2N SO2NH O CH3 USES: Antibacterial agent. ADVERSE EFFECTS: Hypersensitivity skin reactions, crystalluria, METABOLISM: Deamination, Glucuronide conjugation. BRAND NAME: SULFUNO O SYNTHESIS: O H3C ClSO3H H3C -H2O C NH C NH SO2Cl 4-Acetamido benzene sulfonylchloride Acetanilide CH3 N H2N NaOH -HCl O O H3C C NH SO2NH CH3 CH3 N O CH3 CH3 N H2N SO2NH Sulfamoxol O CH3 31 Tetrazole: Tetrazole is a five membered heterocyclic ring containing four nitrogen atoms. N N N N H Examples of drugs: Cefonacid sodium USP, ceforanide USP, cefoperazone, cefmetazole, cefotetan, pentylenetetrazol. Cefonacid (antibacterial antibiotic) Cefoperazone (antibacterial antibiotic) ceforanide (antibacterial antibiotic) cefmetazole (antibacterial antibiotic) pentylenetetrazol CNS stimulant 32 CEFOTETAN: H2NOC S C NaOOC C CH COHN OCH3 S S CH3 N O N C S H2 COONa N N N Cefotetan disodium MOA: It act by inhibiting the synthesis of bacterial cell wall, resulting in cell lysis. Beta lactum antibiotics are structurally similar to D-alanyl-Dalanines(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 O O SYNTHESIS: CS2 H2 C C NaOH COOCH3 COOCH3 NaH HN NH2 S Methyl malonate monoamide SNa Br COO-Na+ ONa OCH3 HN-OCH2C S HCl + N PH N S SNa O CH2OAc 4-Carboxy-3-hydroxy 5-mercapto-isothiazole sodium salt COOH 7 Beta-bromoacetamido7alpha-methoxy cephalosporinic acid CH3 HO COOH N HS N H N S HN-OCH2CS N N NaHCO3 OCH3 S N O CH2OAc COOH H2NOC S C NaOOC C CH COHN OCH3 S S CH3 N N O C S H2 COONa Cefotetan disodium N N N 34 PYRAZOLE: It is a five membered heterocycle containing 2 nitrogen atoms at 1, 2 position. N N H Examples of drugs: Muzolimine, Orisul, antipyrine, phenylbutazone, oxyphenbutazone, sulfinpyrazone, pyrazofurin, tetrazin, metamizole. O C6H5 N C N C H (CH2)3CH3 O Phenyl butazone Antipyrine NSAID Orisul Bacteriostatic N C6H5 HO N O N C H N C O NSAID NO2 H3C OH (CH2)3CH3 Oxyphenbutazone pyrazofurin NO2 butazolidine( NSAID) Phenylbutazone: O C6H5 N C N C H (CH2)3CH3 O Phenyl butazone MOA: Damaged tissue PHOSPHOLIPID phospholipase A2 ARACHIDONIC ACID Cyclooxygenase or prostaglandin synthetase NSAIDS PROSTAGLANDINS Uses: Non-steroidal anti-inflammatory agent . Adverse effects: head ache, digginess, insomnia Metabolism: N-Dealkylation, Aromatic hydroxylation Synthesis: O C6H5 COOC2H5 C H N C + CH3 (CH2)3HH2C COOC2H5 Diethyl-n-butyl malonate N HN HN (CH2)3CH3 O Phenyl butazone Hydrazobenzene 37 PYRROLE: It is a five membered heterocyclic compound containing one nitrogen atom. N H Examples of Drugs : Tolmetin, Zomepirac etc.. H3C C N H CH2COOH O Tolmetin NSAID Chlorophyll Heamoglobin (blood) (pigment) Cyanacobalamine (vitamine) FUSED RING SYSTEMS INVOLVING PYRROLE : INDOLE: vv Tryptophan Ergotamine amino acid antioxytocic Reserpine antihypertensive Vinblastin(anticancer) pindolol (beta-bloker) PYRROLIDINE Nicotine (withdrawal sympoms of tobacco smokers) Phensuximide(CNSdepressant) Procyclidine remoxipride antihistaminic CNS depressant Ethosuximide(CNS depressant) methsuximide (CNS depressant) TOLMETIN: H3C C N H CH2COOH O 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 SYNTHESIS: O + N H H3C CH2CN C AlCl3 Cl 4-Methyl benzoyl chloride 1-Methyl-2-cyanomethyl pyrrole H3C H3C NaOH C N H CH2CN N H C CH2COOH O O Tolmetin metabolised HOOC C O N CH2COOH CH3 Dicarboxylic acid metabolite 41 BARBITURATES BARBITURATES 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. CLASSIFICATION Chemistry of barbiturates: 1. Barbiturates are derivatives of barbituric acid which is devoid of sedative and O OH hypnotic activities. HN N O HO HN N O OH keto-enol tautomerism of barbituric acid 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 O NH2 O H5C2O HN H2N O Urea C2H5ONa C2H5O O HN O Ethylmalonate 2. O Barbituric acid Clinically important hypnotic-sedative barbiturates have substitutions at Sites 1,2 and especially 5 of barbituric acid. 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 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. 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. 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 . 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 Chemical structure of the barbiturates (Seconal) (Pentothal) (Amytal) (Nembutal) (Mebaral) • Phenobarbitone: It occurs as sodium salt. it is hygroscopic, water soluble, bitter taste, odorless, white crystalline power. Synthesis: O O O 1. O O C6H5 Na O CH C O Ethylphenylacetate C C OC2H5 OC2H5 O diethyloxalate O Ethyloxalophenylacetate O O 2. C6H5 CH C C C OC2H5 C6H5 -CO OC2H5 CH C OC2H5 OC2H5 O O C O Ethyloxalophenylacetate C2H5ONa C2H5Br O OC2H5 OC2H5 3. O O O OC2H5 OC2H5 HN urea C2H5 O C6H5 O HN O Phenobarbitone Amobarbitone H3C O O OC2H5 OC2H5 H3C-HC-HC-H2C NH2 HN H2N C2H5 O O CH3 CH2CH2CHCH3 HN O O Amobarbitone Mephobarbital O H3C OC2H5 OC2H5 C6H5 NH2 H2N O N C2H5 O O O C6H5 HN O Mephobarbital • 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