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Medicinal Chemistry 2 Sulfonamides (Sulfa Drugs)

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Medicinal Chemistry 2 Sulfonamides (Sulfa Drugs) Medicinal Chemistry 2 Sulfonamides (Sulfa drugs) Dr. Mamdouh Fawzy Ahmed Faculty of Pharmacy Sohag University Sulfonamides (Sulfa drugs) Antibiotics Definition ❑ 1942, Waksman “an antibiotic is a substance produced by microorganisms which has the capacity of inhibiting the growth & destroying other microorganisms”. ❑ Later “ any substance produced by a living organism that is capable of inhibiting the growth or survival of one or more species of microorganisms in low concs. ❑ medicinal chemists to modify the natural antibiotics to prepare new synthetic analogs so we now have semisynthetic & synthetic derivatives in the definition. Sulfa drugs Sulfa Classification of Antibiotics -Lactam Penicillins & Cephalosporins Aminoglycoside: Streptomycin & Kanamycin Tetracyclines Non- -Lactam Macrolides: Erythromycin & Oleandomycin Polypeptide: Polymixin Polyene: Amphotericin Miscellaneous : Chloramphenicol Sulfonamides (Sulfa drugs) Mechanisms of action of antibacterial drugs [5] 1 Inhibition of Interaction with plasma membrane polymyxins Sulfa drugs Sulfa 2 4 5 Cell wall synthesis Cell metabolism Nucleic acid transcription / replication sulphonamide 1. β-lactam 1. Quinolones 2. Cycloserine 2. Aminoacridines Protein synthesis 3. Rifamycins 1. Tetracyclines 2. Chlormphenicol 3. aminoglycosides Sulfonamides (Sulfa drugs) Bacterial Cell Wall Human cells have no cell wall, but bacterial cells need a cell wall which composed of Peptidoglycan & Proteins. since they have a hypotonic environment in which the cell functions. If no cell wall, bacterial cells would rupture leading to cell death.. Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Discovery: H 2 N N S O 2 N H 2 Sulfa drugs Sulfa N H 2 Prontosil Dye (prodrug) Sulfonamides (Sulfa drugs) Discovery: H2N SO2NH2 In vivo (bacteria) H N N N SO NH + Sulfanilamide Sulfa drugs Sulfa 2 2 2 reductive cleavage H2N NH2 NH2 Prontosil NH2 Sulfonamides (Sulfa drugs) Chemistry of sulfonamide [1] Aniline-substituted [2] Prodrugs giving active [3] Non-aniline sulfonamides sulfonamide sulfonamide O OH O H2N SO2 NH R HN S N N OH SO2 NH CO CH3 Sulfa drugs Sulfa H N Sulfanilamides N O 2 Mafenide acetate Sulfasalazine Sulfonamides (Sulfa drugs) M. O . A of sulfonamide: Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) M. O . A of sulfonamide: Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) M. O . A of sulfonamide: OH OH N CH OPP NH SO NH N CH2 2 2 N Dihydropteroate synthetase N H2N SO2NH2 H N N N 2 H2N N N H H Dihydropteridine Pyrophosphate STOP REACTION O O H2N H2N S NR O O Sulfa drugs Sulfa H-bond H-bond Ionic bond Ionic bond van der Waals van der Waals H H H H N N NH2 NH2 6.7 6.9 C S SO NH O O COOH 2 2 O O p-Aminobenzoic acid Sulfonamide 2.3 2.4 Sulfonamides (Sulfa drugs) M. O . A of sulfonamide: Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) M. O . A of sulfonamide: Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Structure Activity Relationship The 2 functional gps must be para that other positional isomers [m- or o-] are inactive. Free NH2 gp is ESSENTIAL for activity: [1] If substituted by another gp Other substitution on benzene ring NH2 [as alkyl or alkoxy] inactive inactive 4 But, if substituted by a gp that will be converted to NH2 gp in vivo [as NO2,NO, N=N, NHCOR, Other aromatic ring: decrease activity NH-OH] active 1 SO2 NH2 [2] Acylation of N with Dicarboxylic acid as succinic or Sulfa drugs Sulfa Substitution of benzene ring with phthalic acid, give slufonamide NOT absorbed from 5-membered ring cause inactivation. small intestine BUT hydrolyzed in large intestine into [due to different spacingbetween free sulfonamide [Local Intestinal action] the two functional gps] If di-substituted [ -SO2NR2] Inactive If mono-substituted activity Sulfonamides (Sulfa drugs) Structure Activity Relationship H2N SO2NHR A B C Change in A Sulfa drugs Sulfa ❑ Free NH2 is essential for activity. ❑ Removal of NH2 → inactive compounds. ❑ Alkylation of NH2 → inactive compounds. ❑ Shifting NH2 gp to m- or o-position ► inactive compounds. ❑ Substitution with NO2, NHOH, azo or acetylation ► prodrugs which upon reduction or hydrolysis in vivo ► free NH2 (e.g. intestinal sulfa) still retain its activity. Sulfonamides (Sulfa drugs) Structure Activity Relationship H2N SO2NHR A B C Sulfa drugs Sulfa Change in B 1. Phenyl group is essential: replacement with naphthalene, anthracene, pyridine or by another heterocyclic rings or saturation to cyclohexyl → inactive compounds. 2. Substitution on benzene ring by halogen or any other group ► loss of activity. Sulfonamides (Sulfa drugs) Structure Activity Relationship H2N SO2NHR A B C Sulfa drugs Sulfa Change in C 1. SO2 must be directly attached to benzene ring. 2. R should be electron withdrawing group ► ↑ acidity ►↓pKa ► ↑ionization ► ↑activity 3. N is best to be N-acyl “prodrug” this will help in; • Mask the bitter taste (can be used orally as syrup). • Hydrolyzed in vivo to give free active compound. Sulfonamides (Sulfa drugs) Physicochemical properties of sulfa drugs O - H+ O O Ar S NH2 Ar S NH Ar S NH Sulfa drugs Sulfa O O O Sulfonamides (Sulfa drugs) Physicochemical properties of sulfa drugs 2- Amphoteric characters: [with acidic & basic characters] React as acid & base 2 N NH2 basic amino group Amphoteric 1 N SO2NH2 acidic sulfonamide group Sulfa drugs Sulfa O O O H H N S NHR OH 3 H2N S NHR H2N S NR H O O O Resonance stabilized The deprotonated form (in -OH medium) is more stable due to resonance stabilization So, in when we make urine alkaline,we increase solubility [increase ionized form] Sulfonamides (Sulfa drugs) Synthesis of sulfonamides NH NH2 2 NHCOCH 3 NHCOCH 3 NHCOCH 3 NaOH, (Ac) 2O ClSO H 3 RNH2 H2O - HCl SO NRNa SO2Cl SO2NHR 2 NH3 H NHCOCH 3 NH2 Sulfa drugs Sulfa SO NHR SO2NH2 2 2- Solubility of sulfa drugs All sulfonamides are insoluble in water except the sodium salts, on the other hand all sulfonamides are soluble in alkali except sulfaguanidine, while all sulfonamides are soluble in acids. Sulfonamides (Sulfa drugs) Metabolism: O NH 2 NH C CH3 Sulfa drugs Sulfa N-acetyl transferase [less water soluble than parent drug so, make crystalluria] SO NH R 2 SO2 NH R Crystallurea: precipitation of sulfonamide (has low water solubility) which may cause kidney damage Sulfonamides (Sulfa drugs) Crystallurea & PKa Unionized form of the drug pka drug = pH urine + log Ionized form of the drug Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Crystallurea & PKa Unionized form of the drug pka drug = pH urine + log Ionized form of the drug Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Crystallurea & PKa Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Crystalluria & PKa Sulfa drugs Sulfa Sulfonamides (Sulfa drugs) Assay of sulfonamide: 1. Dissolve in dil.HCl & titrate ≠ M/10 NaNO2 diazonium salt. 2. E.p. is determined by ; • KI/starch as external indicator. • Potentiometrically. • Colorimetrically by coupling diazonium salt with -naphthol in NaOH colored compound. Sulfa drugs Sulfa HCl H2N SO2 NHR Cl N N SO2 NHR + H2O + NaCl NaNO2 OH NaOH B-naphthol N N SO2 NHR OH colored compound Sulfonamides (Sulfa drugs) Assay of sulfonamide: [a] Non-aqueous titration [b] Argentometric method [ Back titration] • Add known xss of std. AgNO3 in NaOH insol.Ag Salt + equivalent amount of HNO . • As they are weak acids disslove in 3 • Ag salt is filtered out. pyridine or DMF [basic solvent] & • Either back titration of xss unreacted AgNO3 in Sulfa drugs Sulfa titrate ≠ NaOCH . 3 Filtrate ≠ NH SCN & ferric alum indicator [Volhard] • E.p. determined using thymol blue 4 as indicator. H2N SO2 N R+ AgNO 3 H2N SO2 N R + NaNO3 Na Ag Sulfonamides (Sulfa drugs) Assay of sulfonamide: 1. Add known xss of standard Br2 solution in HCl bromination of sulphonamides. 2. xss Br2 determined by adding KI I2 titrated ≠ std Na2S2O3 e.g. Sulfadiazine NH2 NH2 Sulfa drugs Sulfa Br Br +3 Br2 +3 HBr N N SO2 NH SO2 NH Br N N Sulfonamides (Sulfa drugs) Classification of Sulfonamides Systemic Sulfonamides Topical Sulfonamides Intestinal Sulfonamides [Oral / Absorbable] [Skin / Eye] [Oral / Non-absorbable] [i] Systemic Sulfoanmides Used in treatment of systemic infections. Classified according to rate of excretion [t1/2] into: Sulfa drugs Sulfa SHORT ACTING MEDIUM ACTING LONG ACTING Taken every 6 hrs Taken every 8-12 hrs Taken every 24 hrs t1/2 < 10 hrs t1/2 = 10-24 hrs With slow excretion rate Sulfonamides (Sulfa drugs) Classification of Sulfonamides Systemic Sulfonamides Topical Sulfonamides Intestinal Sulfonamides [Oral / Absorbable] [Skin / Eye] [Oral / Non-absorbable] [i] Systemic Sulfoanmides 1 1 N - Heteroatomic Sulfa drugs Sulfa N -acyl Derivative derivative Pyrimidine Derivatives Pyridazine Derivatives Isoxazole Derivatives Thiadiazole Derivatives Sulfonamides (Sulfa drugs) Classification of Sulfonamides [1] N1-Acyl Derivatives NH2 N-[(4-aminophenyl) sulfonyl ] acetamide OR [N1-acetyl sulphanilamide] SO2 NH CO CH3 Sulfa drugs Sulfa ❑ Water soluble, its solution with pka 5.4 [acidic] risk of crystalluria. ❑ Its Na salt is less alkaline than Na salts of other sulfonamides non-irritant to mucous membrane used as eye drops till 30 % concentration. ❑ Can be used for urinary tract infection [why?] it's highly soluble with t1/2 = 7 hrs [rapid excretion] Sulfonamides (Sulfa drugs) Classification of Sulfonamides [2] N1-Heteroatomic Derivatives [i] Pyrimidine Derivative [ii] Pyridazine Derivative Sulfa drugs Sulfa [iii] Isoxazole Derivative Sulfonamides (Sulfa drugs) Classification of Sulfonamides [2] N1-Heteroatomic Derivatives [i] Pyrimidine Derivative (short acting) NH2 Sulfamethazine t1/2 = 7 hrs / pka = 7.2 More water soluble > sulfadiazine & CH 3 sulfamerazine in acidic urine [pH=5.5], but N lower activity in vitro & in vivo. SO NH 2 Used in combination sulfa [Tri-sulfapyrimidine N therapy] CH3 Sulfa drugs Sulfa N1( 4,6-dimethyl- 2- pyrimidinyl ) Sulphanilamide NH2 Sulfisomidine CH3 t1/2 = 7.5 hrs SO2 NH N The most water soluble of pyrimidine N derivatives tendency of crystalluria. CH3 N1( 2,6-dimethyl- 4- pyrimidinyl ) Sulphanilamide Sulfonamides (Sulfa drugs) Classification of Sulfonamides [2] N1-Heteroatomic Derivatives [i] Pyrimidine Derivative (moderate or intermediate acting) Sulfadiazine NH2 t1/2 = 17 hrs / pka = 6.3 Broad spectrum, the drug of choice in UTI.
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