Medicinal Chemistry I PDF

Medicinal Chemistry I PC 505 PC 507 Non -lactam Antibiotics Presented by: Non -lactam Antibiotics This includes different subclasses: Tetracyclines Aminoglycosides Chloramphenicol Macrolides Sulf...

Medicinal Chemistry I PC 505 PC 507 Non -lactam Antibiotics Presented by: Non -lactam Antibiotics This includes different subclasses: Tetracyclines Aminoglycosides Chloramphenicol Macrolides Sulfonamides ??(Antibacterial) However,The antibiotic penicillin is renowned as the "Queen of Medicines." Penicillins (P, PCN, or PEN) are antibiotics that were first discovered in Penicillium moulds, particularly P. chrysogenum and P. rubens. The majority of penicillins used in medicine are chemically synthesized from penicillins found in nature. Non -lactam Antibiotics8 7 6 5a 5 4a 4 3 D C B A 1.Tetracyclines 9 2 11a 12a Obtained from: Fermentation procedures from 10 11 12 1 Streptomyces species. Octahydronaphthacene Chemical transformation of natural products. Naphthacene Octahydronaphthacene [5 double bonds] Bacteriostatic Broad spectrum antibiotic (effective against G+ve, G-ve bacteria, Rickettsiae, Mycoplasma, Chlamydia & H3C CH3 OH N Cholera). H3C H H Acute intestinal amoebiasis. OH Plasmodium falciparum infections that are resistant to anti-malarial drugs. OH Bacillary dysentery. NH2 Acne [suppress both skin bacteria & their lipases which promote inflammatory changes]  used in low doses OH O OH O O for many months. treat eye infections (Ophthalmic tetrcyclines), pneumonia (T.C. for Tetracycline pneumonia), gonorrhea, for urinary tract infections  Mechanism of Action 1.Tetracyclines Bacteriostatic action: bind to 30 S ribosomal subunit of bacteria  block access of amino acyl t-RNA to m-RNA complex at the acceptor site  inhibition of protein synthesis. H3C CH3 OH N H3C H H OH OH NH2 OH O OH O O  ( chemistry mechanism of action drug binds to the ribosomal binding site ( 30S ) by forming a chelate compound with the magnesium ion that present at the binding site → blocking amino acyl t RNA ( prevented from bringing another amino acids ) → inhibition of protein synthesis  Mechanism of Action 1.Tetracyclines N(CH3)2 Bacteriostatic action: You can Resize without OH losing quality You can Change Fill NH2 The binding of aminoacyl tRNA and the Color & Line Color OH binding of tetracyclines at the ribosomal- O M O OH O O binding site both require magnesium ion. The strong binding properties of the tetracyclines with metal ions suggests that FREE their antibacterial properties may be PPT because of an ability to remove essential TEMPLATES metal ions as chelated compounds. www.allppt.com  Adverse Effects 1.Tetracyclines OH H3C N CH3 1.Gastric discomfort (from irritation of gastric H3C You H can Resize without H OH mucosa)  so, taken with food. losing quality OH You can Change Fill NH2 2.Deposition in bone & teeth during calcification in Color & Line Color OH O OH O O growing children (due to chelation with Ca2+)  discoloration & hypoplasia of teeth so They are not recommended for pediatrics less than 8 years of age or pregnant women. Causes teeth discoloration in the fetus. FREE 3.Super infections: overgrowth of Candida in vagina PPT or resistant Staphylococci in intestine. TEMPLATES 4.Outdated tetracycline may produce renal www.allppt.com damage. 5. Photosensitive allergic reaction  CH3 CH3 H3C OH N SAR H H 7 H5a 5 4a 4 6a 3 8 6 OH D C B 12a A 9 CONH2 H3C CH3 2 10 11 11a 1 N 12 OH OH O OH O H OH H OH NH2 OH O OH O O Pharmacophore of this group is Sancycline (it’s with full biological activity but clinically NOT an important antibiotic).  SAR Strong electron withdrawing groups e.g., Cl, NO2 Strong electron donating e.g., dimethylamino at position 7 enhance the activity  SAR of tetracyclines 1) four cycles (rings) 2) dimethylamine group ( in alpha position) 3) OH at position 6 could be removed because it causes an interaction in acidic medium 4) conjugated system of the ( OH-O-OH-O ) ( double - single) ( the system keto-ethanol ring D ) 5) the (OH) with carboxyamide (CNH2) and double bond (0) ,substitution of the amide by aldehyde or nitrite reduces the activity 6) Modifications at positions 1 , 3 , 4A , 10 result in loss of activity SAR  Chemical Stability 1.Tetracyclines H3C CH3 A)Action of strong acids-Dehydration at C6: OH N You can Resize without H3C H H losing quality OH Occurs in presence of strong acids stomach acidity You can Change Fill Color & OH NH2 (for tetracyclines with 6-OH) Line Color OH O OH O O 7 6 5 4 5a 4a 8 3 D C B A 9FREE 12a 2 11a PPT 10 11 12 Octahydronaphthacene 1 Aromatization TEMPLATES [5 double bonds] N.B: Tetracyclines without 6-OH: www.allppt.com 1.RESIST ACTIONS OF ACIDS & BASES. 2.HIGHER LIPID SOLUBILITY & SO, BETTER ABSORPTION.  CH3 N(CH3)2 Chemical Stability H OH CONH2 1.Tetracyclines OH OH O O 4-epianhydrotetracyclines H3C CH3 B)Epimerization at C4: toxic to the kidneys 4-epianhydrotetracyclines a degradation product OH N You can Resize without H3C H H losing quality OH Occur at intermediate pH (pH=2-6) especially in You can Change Fill Color & OH NH2 solutions. Line Color Leads to formation of 4-Epimertetracycline OH O OH O O (i.e:with -configuration)  Inactive. [alpha] [beta] 7 6 5 4 H+ N(CH3)2 H 5a 4a H N(CH3)2 N(CH3)2 8 3 OH OH OH D C B A + FREE 9 12a 2 -H - H+ 11a NH2 NH2 NH2 PPT 10 11 12 Octahydronaphthacene 1 + +H + H+ OH OH OH - TEMPLATES [5 double bonds] O O O O O O Tetracycline 4-Epitetracycline www.allppt.com [active] [inactive] Toxic to kidney  Chemical Stability 1.Tetracyclines H3C CH3 C)Action of Bases : OH N You can Resize without H3C H H losing quality OH Basic medium inactivates tetracyclines having 6-OH You can Change Fill Color & OH NH2 gp to give Isotetracycline (lactone). Line Color OH O OH O O H3C CH3 OH H3C CH3 OH H3C CH3 CH3 N N H3C N H H3C H H OH 7 6 5 4 OH OH 5a 4a OH- 8 3 O OH OH D C BOH A FREE 9 2 12a CONH CONH2 CONH2 11a 2 PPT 10 11 OH O 12 1 OH OOctahydronaphthacene OH O O O OH O O O TEMPLATES [5 double bonds] Tetracycline Isotetracycline www.allppt.com inactive lactone Active structure is not 4 fused rings  Chelation 1.Tetracyclines N(CH3)2 Chelation & Incompatibilty: You can Resize without OH Tetracyclines show incompatibility with polyvalent metal ions as losing quality You can Change Fill NH2 Fe+2, Ca+2, Mg+2, Al+3 present in preparations. Color & Line Color OH Problem: when co-administered with milk, antacids or anti- O O OH O O anemics. This is due to chelation through the poly oxygenated M bottom by forming insoluble non-absorbable salts in GIT Solution: to avoid that, take ion preparation 1 hr before or 7 6 5 4 2 hrs after taking tetracyclines. 5a 4a 8 A 3 Problem: They are painful upon I.M. injection: due to D C B 9FREE 12a 2 chelation with Ca+2 present in muscles  insoluble complex 11a PPT 10 11 12 1  precipitation  pain & irritation. Octahydronaphthacene TEMPLATES [5 double bonds] Solution: Add EDTA to injectable product to form water soluble www.allppt.com complex with Ca+2 & so, no available Ca+2 for chelation. OR add Buffer solution at acidic pH, chelation is less & water solubility of the complex .  Therapeutic Potential for COVID-19 Treatment You can Resize without Coronaviruses highly rely on host (MMPs) losing quality You can Change Fill for survival & replication. Tetracycline may limit Color & Line Color replication of COVID-19 and help in inhibiting COVID-19 infection in human. HOW??? Tetracycline (Highly lipophilic) can chelate zinc compounds on MMPs. FREE PPT TEMPLATES www.allppt.com an enzyme that helps Covid to entering human cells N.B: Matrix metalloproteinases (MMPs)(a family of calcium (Ca2+)- and zinc (Zn2+)-dependent proteolytic enzymes) Further research is required to investigate potential of tetracycline in treating COVID-19.  SAR H3C CH3 N H OH H OH NH2 OH O OH O O Pharmacophore of this group is Sancycline (it’s with full biological activity but clinically NOT an important antibiotic).  SAR Strong electron withdrawing groups e.g., Cl, NO2 Strong electron donating e.g., dimethylamino at position 7 enhance the activity  Classes of Tetracyclines 1.Natural Tetracyclines H3C CH3 OH N You can Resize without H3C H H A)Tetracycline H3C OH H H3C N CH3 H losing quality OH Most widely used in OH You can Change Fill OH Color & OH tetracyclines, cheap antibiotic. NH2 NH2 Line Color Drug of choice in treatment of OH O OH O O OH O OH O O acne. Chemical Name: 4-Dimethylamino-1,4,4a,5,5a,6,11,12a-octahydr- B)Chlortetracycline Cl CH3 OH H3C N CH3 H 3,6,10,12,12a-pentahydroxy-6-methyl-1,11- dioxo-2-naphthacene carboxamide. 7-chloro is hydrophobic e- OH OH withdrawing gp that  activity. CONH2 7 6 5 4 8FREE OH O OH O 5a 4a 3 A D 9PPT C B 2 C)Oxytetracycline OH H3C OH N CH3 11a 12a H3C H 10 TEMPLATES 11 12 1 Octahydronaphthacene [Terramycin®] OH OH [5 double bonds] www.allppt.com The most hydrophilic tetracycline CONH2 OH O OH O  Classes of Tetracyclines 2.Semi-SyntheticTetracyclines H3C CH3 H3C CH3 A)Doxycycline H OH N OH N You can Resize without H3C H H3C losing H quality H OH (Vibramycin®) OH You can Change Fill OH it's excreted through feces not the kidney OH Color & NH2 Line Color Thus doxycycline can be given CONH2 OH O OH O O to uremic patients with OH O OH O Chemical Name: infections outside the urinary 4-Dimethylamino-1,4,4a,5,5a,6,11,12a-octahydr- tract. 3,6,10,12,12a-pentahydroxy-6-methyl-1,11- urinary tract infection dioxo-2-naphthacene carboxamide. Its metabolite is preferentially excreted via bile into feces, it may 7 6 5 4 be used in those with renal impairment. 8FREE 5a 3 4a D C B A It is used in prophylaxis against malaria. 9PPT 2 Doxycycline is frequently used to treat sinusitis, acne and Rikettsial 11a 12a 10 TEMPLATES 11 12 1 Octahydronaphthacene infections. [5 double bonds] www.allppt.com  Classes of Tetracyclines 2.Semi-SyntheticTetracyclines OH H3C N CH3 B)Minocycline You can Resize without H3C CH3 H3C H H H3C CH3 losing quality OH More lipophilic, gives excellent N N You can Change Fill H Color & OH blood levels following oral OH NH2 Line Color administration and can be given OH OH O OH O O once a day. CONH2 Chemical Name: 4-Dimethylamino-1,4,4a,5,5a,6,11,12a-octahydr- It has vestibular toxicities (vertigo, OH O OH O 3,6,10,12,12a-pentahydroxy-6-methyl-1,11- dioxo-2-naphthacene carboxamide. ataxia and nausea) 7 6 5 4 More lipophilic, Why ??  better oral administration. 8FREE 5a 3 4a Given once daily [long duration]. D C B A it has no 6-0H ( tetracycline without 6-0H ) 9PPT 2 With Broad spectrum 11a 12a 10 Stable against acids & bases [why?]. used in treating of meningitis TEMPLATES 11 12 1 Octahydronaphthacene [5 double bonds] www.allppt.com Although all tetracyclines enter CSF, levels are insufficient for therapeutic efficacy, except for Minocycline.  Classes of Tetracyclines Semi-Synthesis of Minocycline H3C CH3 H3C CH3 N N H3C CH3 H3 C CH 3 You can Resize without H OH Cl OH N N losing quality H H You can Change Fill OH OH OH catalytic reduction Color & OH OH CONH2 Line Color CONH2 CONH 2 OH O OH O OH O OH O OH O OH O Demeclocycline Sancycline Nitration H 3C CH 3 H3C CH3 H3C CH3 N N NO2 N 7 6 5 4 H H 8FREE 5a 4a OH OH 3 reductive methylation D C B A 9PPT OH OH 2 HCHO 11a 12a CONH2 CONH2 10 TEMPLATES 11 12 1 Octahydronaphthacene OH O OH O OH O OH O [5 double bonds] www.allppt.com Minocycline  Classes of Tetracyclines 3. Tetracycline Analogue Tigecycline You can Resize without losing quality You can Change Fill Color & Line Color FREE PPT TEMPLATES It is a synthetic derivative Glycylcycline is a Tetracycline Analogue antibiotics have a similar mechanism of action as tetracycline antibiotics. of minocycline www.allppt.com They overcome two common mechanisms of tetracycline resistance (Acquired efflux pumps and/or ribosomal protection yet they aren’t active against pseudomonas  Contraindicated to?? 1.Tetracyclines H3C CH3 OH N Patients? H3C H H You can Resize without OH losing quality OH You can Change Fill NH2 Color & Line Color OH O OH O O Age? Women? FREE PPT TEMPLATES www.allppt.com Non -lactam Antibiotics Aminoglycosides Presented by:  Non -lactam Antibiotics 2.Aminoglycosides  Non -lactam Antibiotics 2.Aminoglycosides Obtained from M.O. in the soil: either Streptomyces (end with You can Resize without suffix mycin) or Micromonospora (end with suffix micin). losing quality Prototype of this class (first one used) is Streptomycin. You can Change Fill Color & BACTERICIDAL, against Aerobic bacteria only. Line Color Although broad spectrum, but of limited use for only severe G-ve infections. Due to their high toxicity [cause ototoxicity by action on 8th cranial nerve and nephrotoxicity]. They are basic (due to amino group)  Freely water soluble  FREE Very poorly absorbed from GIT  used by injection. PPT When used orally it's intended for local GIT infections. TEMPLATES Neomycin must not be given parentrally (of high toxicity), only www.allppt.com used topically or orally in hepatic coma to  intestinal bacterial population.  Physicochemical Properties 2.Aminoglycosides The aminoglycosides are thus strongly basic compounds that exist as polycations at physiological pH. Their inorganic acid salts are very soluble in water. Not absorbed from GIT due to its highly polar structure and are excreted in active form in fairly high concentration in the urine following injection. Under certain conditions, aminoglycosides and β–lactam antibiotics exert a synergistic action, but the two antibiotics must not be combined in the same solution and should be given into different tissue compartments (usually one in each arm) because they are chemically incompatible (N-acylation of aminoglycosides by the β–lactam).  Physicochemical Properties 2.Aminoglycosides CO2H NH ROCHN O ROCHN HN Aminoglycoside N sugar-O + O CO2 (active) HO NH2 O-sugar B-lactam antibiotic Inactive (active)  Mechanism of Action 2.Aminoglycosides Inhibition of protein synthesis: Bind to 30 S ribosomal You can Resize without subunit of M.O.  inhibit initiation of protein synthesis losing quality You can Change Fill  bactericidal action. Color & Line Color FREE PPT TEMPLATES www.allppt.com  Bacterial Resistance 2.Aminoglycosides 1. Permeability defect: by outer membrane change  You can Resize without losing quality  active transport into cell  drug can't reach You can Change Fill Color & ribosome. Line Color 2. Lack of specific protein receptor on 30 S subunit  lower affinity of binding site to aminoglycosides. 3. Production of enzymes (R-factor Enzymes) that destroy drugs: Acetyl transferase enzyme: make acetylation of FREE NH2 group. PPT Phosphoryl transferase enzyme: make TEMPLATES phosphorylation of OH group. www.allppt.com Adenyl synthetase enzyme : make O-adenylation.  SAR 2.Aminoglycosides NH2 H2N OH NHCH3 C NH A)Streptidine NH N-methyl YouHOcan ResizeO without NH HN glucosamine losing quality OH 2 HOH2C O HO 3 OH You can Change Fill O NH NH2 NH NH2 Color & OHC OH C HO 1 HO OH Line Color O NH NH HO Streptidine L-Streptose CH3 B)2-deoxy H2N streptamine HO PHARMACOPHORIC HO NH2 UNIT is 1,3-DIAMINO OH FREE MOIETY INOSITOL PPT [aminocyclitol unit]. C)Spectinamine H3C-HN HO From this moiety ; we TEMPLATES HO have 3 pharmacophoric www.allppt.com HO NH CH3 groups: OH  Aminoglycosides A)Aminoglycosides with Streptidine OH NH-CH3 H2N 1.Streptomycin HO H2N NH O NH You can Resize without HNquality losing HOH2C HN 2 HOYou can 3Change Fill OH O O OH Color & N-methyl glucosamine NH NH2 HO Color Line 1 NH NH2 [amino sugar] HO OH CH3 O HO NH OH NH OHC Streptidine Streptidine -CH2-OH [Pharmacophore] L-Streptose Dihydro Streptomycin [neutral sugar] PHARMACOPHORIC UNIT is 1,3-DIAMINO Streptobiosamine [Disaccharide] FREE MOIETY INOSITOL PPT [aminocyclitol unit]. Basically for T.B., replaced now by other antibiotics as Rifampin. From this moiety ; we Dihydro streptomycin: Formed by replacing aldehydic group in L- TEMPLATES streptose moiety by alchoholic group [CH2OH]. With greater have 3 pharmacophoric www.allppt.com probability than streptomycin to cause delayed deafness. groups:  Aminoglycosides B)Aminoglycosides with 2-deoxy Streptamine Ring II 1.Kanamycin R1 NH2 NH2 OH Ring You can Resize without Ac 2-Deoxystreptamine I HO O 4' 6' losing 6'-glucosamine HO quality NH2 5' O O O O Ad HO HO HO You can Change R2 Fill HO 1' H HO H HO H 3' 2' Color & HO NH2 OH 4 H N NH2 NH2 O O 2 3 2 O O R1 Line R2 Color Phos -CH2NH2 -OH Kanamycin A HOH2C Ring III 6 1 NH Kanmycin B Kanmycin C O OH HO 2 -CH2NH2 -NH2 Kanamycin B 3''-glucosamine -NH2 Kanamycin C HO 5 Glycosidic linkage -CH2OH (kanosamine) O H2N 5'' 1'' HO 6'' 2-deoxy Streptamine O OH Kanmycin A HO 3'' 4'' H2N 2'' Mixture of Kanamycin A, B & Unstable to R-factor enzymes: (giving INACTIVE compounds) C.FREE [according to D-glucose –3'-OH  Phosphorylation. 4'-OH  Adenylation. 6'-NH2  Acetylation. PPT attached to 4-position of 2- deoxy streptamine]. To improve its activity  SEMI-SYNTHETIC PRODUCTS by: TEMPLATES Commercially available Adding functional group that prevent enzymatic attack. Kanamycin is pure Kanamycin www.allppt.com Removal of susceptible functional groups which are not important for A [the least toxic of them]. activity.  Aminoglycosides B)Aminoglycosides with 2-deoxy Streptamine R1 Ring II 2. Amikacin Ring You can Resize without (Amikin®) O 2-Deoxystreptamine I HO NH2 Ac losing quality NH2 4' 6' 6'-glucosamine HO O 5' O You can Change R2 Fill Ad X HO 1' H HO Color & HO NH2 3' 2' R1 Line R2 Color O X OH O 4 H N 2 3 2 O OH Phos -CH2NH2 -OH Kanamycin A HOH2C O OH Ring III 6 1 NH -CH2NH2 -NH2 Kanamycin B 3''-glucosamine HO C CH CH2 CH2 NH2 -CH2OH -NH2 Kanamycin C HO (kanosamine) 5 H2N O 1'' L-AHBA 2-deoxy Streptamine HO O HO OH 2'' H2N Semi-synthetic analogue of Kanamycin A  produced by FREE acylation of 1-amino group with L-AHBA [L--Amino-α-Hydroxy PPT Butyric Acid]. Advantages: TEMPLATES Less toxic than Kanamycin or Gentamicin. www.allppt.com L-AHBA   binding to R-factor mediated enzymes  prevent adenylation at C4' & phosphorylation at C3'   potency & broaden spectrum.  Aminoglycosides B)Aminoglycosides with 2-deoxy Streptamine Ring II 3. Tobramycin R1 NH2 Ring You I can Resize HO losing 6'-glucosamine HO O quality without 2-Deoxystreptamine NH2 (Deoxy Kanamycin B) 4' 6' 5' O Ac O Ad HO You can Change Fill R2 1' H X Color & HO NH2 3' 2' O 4 H N R1 Line R Color NH2 O 2 3 2 Phos 2 -CH2NH2 -OH Kanamycin A HOH2C O OH Ring III -CH2NH2 -NH2 Kanamycin B 3''-glucosamine 6 1 NH -CH2OH -NH2 Kanamycin C HO (kanosamine) HO 2 H2N 5 O 2-deoxy Streptamine 1'' HO O HO OH H2N 2'' FREE Lack 3'-OH  resist O-phosphorylation  broader PPT spectrum > Kanamycin. TEMPLATES But, can be adenylated & acylated  inactivation. www.allppt.com Active against most strains of Pseudomonas aeruginosa [> Gentamicin by 2-4 folds].  Aminoglycosides B)Aminoglycosides with 2-deoxy Streptamine Ring II 4. Gentamycin R1 Ring You I can Resize HO losing 6'-glucosamine HO O quality without 2-Deoxystreptamine NH2 (Garamycin®) O NH CH3 NH2 NH2 You can Change R2 Fill H3C H3C CH 6' Ac H2C 6' CH 6' Color & X HO NH2 4' 4' 4' Ad 5' 5' 5' O O O O R1 Line R2 Color -CH2NH2 -OH Kanamycin A HOH2C Ring III 1' H 1' H 1' H O OH X -CH2NH2 -NH2 Kanamycin B 3' 2' 3' 2' 3' 2' 3''-glucosamine 4 H N -CH2OH -NH2 Kanamycin C HO (kanosamine) NH2 O 2 3 2 NH2 O NH2 O Phos H2N 6 1 NH HO 2 Gentamicin C1a Gentamicin C2 5 2-deoxy Streptamine O Gentamicin C1 1'' O 3HC OH 2'' HN HO CH3 Garosamine Suger: specific for all Gentamicins FREE PPT Lack 3'-OH & 4'-OH  resist R-factor enzymes TEMPLATES [broader spectrum], but inactivated at other www.allppt.com sites.  Aminoglycosides B)Aminoglycosides with 2-deoxy Streptamine Ring II 5.Neomycin R1 Ring You can Resize without 2-Deoxystreptamine I O NH2 HO losing quality NH2 Same as Kanamycin B 6'-glucosamine HO O [6-amino-6-deoxy glucosamine] You can Change R2 Fill HO O Color & HO NH2 O R1 Line R2 Color HO -CH2NH2 -OH Kanamycin A HOH2C O OH Ring III -CH2NH2 -NH2 Kanamycin B 3''-glucosamine H2 C NH2 NH2 H2 N -CH2OH -NH2 Kanamycin C HO (kanosamine) H2N O O 4 HO OH HO NH2 2-deoxy Streptamine O 5 H2C O OH NH2 O fourth ring [Pentose sugar] OH FREE PPT THE MOST TOXIC AMINOGLYCOSIDE  NOT taken systemically. does not reach the blood circulation system TEMPLATES www.allppt.com Uses: mainly in dermatological infections and GIT infections.  Aminoglycosides B)Aminoglycosides with Spectinamine OH NHCH3 1. Spectinomycin O You can Resize1without O losing quality OH (Trobicin®) O NHCH3 You can Change Fill Color & OH. Spectinamine contains two mono N-methyl groups and the O Line Color hydroxyl between them has a stereochemistry opposite to that in Spectinamine streptomycin. CH3 Spectinamine Bacteriostatic. It's the drug of choice in treatment of GONORRHEA cause by penicillinase- FREE producing N. gonorrhea. PPT TEMPLATES www.allppt.com Aminoglycosides Antibiotics Insert the Subtitle of Your Presentation http://www.free-powerpoint-templates-design.com THANK YOU