1. 1 Lecture 6 Medicinal Chemistry 1 (PC 509) Prof. Dr/ Ghaneya Sayed Hassan ghanmoom2@yahoo.com

2. 2 Aminoglycosides  They are antibiotics obtained from m.o. in the soil: (1) Streptomyces [end with suffix mycin]. (2) Micromonospora [end with suffix micin].  Prototype of this class [first one used] is Streptomycin. M.O.A: [inhibition of bacterial protein biosynthesis] Irreversibly binding the 30S ribosomal subunit of m.o. through specific receptor protein  inhibit initiation of protein synthesis  cause misreading of genetic code on recognition region of ribosome  insertion of wrong amino acids  non-functional protein [anti- sense protein]  destruction of cell membrane  bactericidal action. Warning Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use.

3. 3 General properties: 1)They are BACTERICIDAL, effective only ≠ aerobic bacteria [they are inactive ≠ anaerobic bacteria that transport through cell membrane is energy-requiring process that is oxygen-dependent]. 2) They are limited use and for only severe G-ve infections due to their  toxicity [cause ototoxicity & nephrotoxicity by action on 8th cranial nerve]. 3) Freely water soluble  used by injection. But Neomycin must not be given parentrally [  toxicity], only used topically or orally in hepatic coma to  intestinal bacterial population. 4) Very poorly absorbed from GIT [highly polar compounds]  when used orally it's intended for local GIT infections. But given I.M. for systemic infections. There is no oral form available as aminoglycosides are not absorbed orally

4. 4 5) Aminoglycosides +  -lactams  synergism but must not be combined in the same solution [should be given into different tissue comportments, as given each preparation one in each arm]  they are chemically incompatible. Inactivate if put with β-lactam antibiotics in same preparation  N- acylation by β-lactam ring  inactivation of both antibiotics. 6) Aminoglycosides can exacerbate weakness in patients with myasthenia gravis, and use is therefore avoided in these patients

5. 5 Resistance: There are three mechanisms: (1)Reduced uptake or decreased cell permeability: Permeability defect: by outer membrane change   active transport into cell  drug can't reach ribosome. (2) Alterations at the ribosomal binding sites: Lack of specific protein receptor on 30 S subunit  lower affinity of binding site to aminoglycosides. (3) Production of aminoglycoside modifying enzymes: Several of the aminoglycoside antibiotics can be inactivated by enzymes which occur in gram-negative bacteria carrying R-factors. R-factor genes mediated the formation of aminoglycoside-inactivating enzymes 1-Aminoglycoside 6'-N-acetyltransferase: enzymes make acetylation of NH 2 group. (ANT) 2-O-Phosphoryl transferase: enzymes make phosphorylation of OH group. (APT) 3- O-Adenyl transferase : enzymes make O-adenylation. (AAT) Inositol (Cyclhexanhexaol)

6. 6 Chemical properties: Pharmacophoric unit is 1,3-diamino Inositol moiety “ aminocyclitol unit”. From this moiety ; we have 3 pharmacophoric groups : Spectinamine2-deoxy streptamineStreptidine (1) Alcoholic functions of these moieties [OH]  make glycosidic bonds with characteristic amino sugars [aminoglycosides]. (2) They are usually formed of 3 rings, freely soluble in water [why?] (3) They are basic [due to amino group], form acid addition salts.

7. 7 [I] Aminoglycosides containing Streptidine Streptomycin

8. 8 Produced by Streptomyces griseus. Basic, water soluble [available as sesquisulfate salt which is quite soluble in water]. With hydrophilic nature  poorly absorbed from GIT [usually taken I.M.] M.O.A: Inhibition of protein synthesis + misreading of m- RNA & membrane damage. Diffuse across outer membrane of T.B.  penetrate cytoplasmic membrane through electron-dependent process. Uses: (1) Bactericidal [I.M  limit its use in long-course therapy] (2) Used in combination for T.B. + other infections.

9. 9 SAR: (1)Reduction of aldehyde to alcohol  Dihydrostreptomycin [similar activity but with delayed severe deafness]. (2) Oxidation of aldehyde to carboxyl or conversion to Schiff's base [oxmie, semicarbazone, phenyl hydrazone]  inactive (3) Oxidation of Methyl group in  -streptose to methylene hydroxyl  active but with no advantage over STM. (4) Demethylation or replacement of amino methyl in glucosamine part with larger alkyl group   activity. (5) Removal or modification of either guanidine   activity.

10. 10 ► Produced by fermentation of Sterptomyces griseus & related soil m.o. ► Introduced primarily for treatment of T.B.[ may be due to presence of two guanido moieties]. But replaced now by other antibiotics as Rifampin. Dihydro streptomycin: Formed by replacing aldehydic group in L-streptose moiety by alchoholic group [CH 2 OH] With greater probability > streptomyces to cause delayed deafness.

11. 11 [ii] Aminoglycosides containing 2-deoxy Streptamine [i] 4,6-di-O-glycosyl substitution Kanamycin

12. 12 ■ Isolated from Streptomyces kanamyceticus  mixture of Kanamycin A, B & C. [according to D-glucose attached to 4-position of 2-deoxy streptamine]. ■ Commercially available Kanamycin is pure Kanamycin A [the least toxic of them]. ■ Chemically stable within pH of 2-11, very stable to heat [sterilized by autoclaving]. ■ Unstable to R-factor enzymes: [giving INACTIVE compounds] 3'-OH  Phosphorylation. 4'-OH  Adenylation. 6'-NH 2  Acetylation. ■ To improve its activity  SEMI-SYNTHETIC PRODUCTS by: (1) Adding functional group that prevents enzymatic attack. (2) Removal of susceptible functional groups which are not important for activity.

13. 13 Amikacin [Amikin ® ] Semi-synthetic aminoglycosides L-  -Amino-α-Hydroxy Butyric Acid The side chain protects amikacin from attack by steric hindrance or folding

14. 14 Semi-synthetic analogue of Kanamycin A  produced by acylation of 1-amino group with L-AHBA [L-  -Amino-α-Hydroxy Butyric Acid]. Advantages: (1) Less toxic than Kanamycin or Gentamicin. (2) L-AHBA   binding to R-factor mediated enzymes  prevent adenylation at C4' are phosphorylation at C3‘   potency & broaden spectrum. Amikacin is resistant to many R-factor mediated enzymes due to the presence of L-AHBA [L-  -Amino-α-Hydroxy Butyric Acid]. Uses: serious infections by bacteria those are resistant to other aminoglycosides

15. 15 Gentamicin [Garamycin ® ]  Produced by fermentation of Micromonspora purpurea & other related soil m.o. [mixture of compounds]

16. 16 Uses: 1- Has significant activity ≠ Pseudomonas aeroginosa infections [in burns, pneumonias & UTI], also, prevent fouling of soft contact lenses. 2- It is not effective for gonorrhea or chlamydia infections. 3- Gentamicin is also used in molecular biology research as an antibacterial agent in tissue and cell culture, to prevent contamination of sterile cultures. Gentamicin is one of the few heat-stable antibiotics that remain active even after autoclaving, which makes it particularly useful in the preparation of some microbiological growth media

17. 17 [iii] Aminoglycosides with Spectinamine Spectinomycin  Produced by fermentation of Streptomyces spectabilis.  Composed of Spectinomine moiety + bicyclic moiety fused at 4-OH & 5-OH. [with only one sugar].  The interaction of Spectinomycin with the 30S-ribosomal subunit is reversible.  Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides. It lacks amino sugars.

18. 18 M.O.A: Interfere with binding t-RNA to ribosomes  interfere with initiation of protein synthesis [as Streptomycin], BUT, NOT cause misreading of messenger [≠ Streptomycin]  Bacteriostatic NOT Bactericidal effect. Uses: (1) Alternative to penicllins, that it not cause serious oto- or nephrotoxicity. (2) It's the drug of choice in treatment of GONORRHEA cause by penicillinase-producing N. gonorrhea.