Medicinal Chemistry (Aminoglycoside Antibiotics) PDF

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/321938027 MEDICINAL CHEMISTRY (Aminoglycoside Antibiotics) Presentation · December 2017 DOI: 10.13140/RG.2.2.19507.32801 CITATIONS...

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/321938027 MEDICINAL CHEMISTRY (Aminoglycoside Antibiotics) Presentation · December 2017 DOI: 10.13140/RG.2.2.19507.32801 CITATIONS READS 0 21,494 1 author: Dr Sumanta Mondal GITAM (Deemed to be University) 326 PUBLICATIONS 937 CITATIONS SEE PROFILE All content following this page was uploaded by Dr Sumanta Mondal on 20 December 2017. The user has requested enhancement of the downloaded file. PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Aminoglycoside Antibiotics - Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). - The term can also refer more generally to any organic molecule that contains amino-sugar substructures. - The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds. - Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance against Gram-positive and anaerobic Gram-negative bacteria. - Streptomycin, the first antibiotic of this group. - Adverse effect: The aminoglycoside can produces severe adverse effects, which include nephrotoxity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications. - Mode of action: The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Ribosomal binding on 30s and 50s subunits as well as the interface produces misreading; this disturbs the normal protein synthesis. Cell membrane damage also plays an integral part in ensuring bacterial cell death.  Examples of aminoglycoside antibiotics Name Source Streptomycin Streptomyces griseus Neomycin S. fradiae Kanamycin S. kanamyeleticus Gentamycin Micromonospora purpura Netilmicin Micromonospora species Tobramycin S. tenebrarius Framycetin S. decaris Paromomycin S. rimosus and S. paramomycinus Amikacin It is 1-L-(-) 4-amino-2-hydroxy butyryl kanamycin Lecturer Notes_Dr. S. Mondal_B. Pharm 6th Semester_GITAM (Deemed to be University) Page | 1 E-mail: [email protected] PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Aminoglycoside Antibiotics  Streptomycin: It is used in the treatment of infections caused by gram-negative bacteria of particular interest and has a high degree of activity against P. aeruginosa, where the important causative factor is burned skin. It is used topically in the treatment of infected bed-sores, pyodermata, burns, and in the eye infection.  Neomycin: It is photosensitive and its main use is in the treatment of the ear, eye, and skin infections; these include burns, wounds, ulcer, and infected dermatoses. Lecturer Notes_Dr. S. Mondal_B. Pharm 6th Semester_GITAM (Deemed to be University) Page | 2 E-mail: [email protected] PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Aminoglycoside Antibiotics  Kanamycin: The kanamycins do not possess D-ribose molecule. The use of kanamycins is restricted to infections of the intestinal tract and to systemic infections.  Tobramycin: Its activity is similar to gentamycin. The superior activity of tobramycin against P. aeruginosa may make it useful in the treatment of bacterial oesteromyelitis, and pneumonia caused by Pseudomonas species. Lecturer Notes_Dr. S. Mondal_B. Pharm 6th Semester_GITAM (Deemed to be University) Page | 3 E-mail: [email protected] PPH 308: MEDICINAL CHEMISTRY - II Unit: II: Aminoglycoside Antibiotics  SAR of Aminoglycoside Antibiotics - The aminoglycosides consist of two or more amino sugars joined in glycoside linkage to a highly substituted 1,3- diaminocyclo hexane (aminocyclitol), which is a centrally placed ring. The ring is a 2-deoxy streptamine in all aminoglycosides except streptomycin and dihydrostreptomycin, where it is streptidine. Thus,  In kanamycin and gentamycin families, two amino sugars are attached to 2-deoxy streptamine.  In streptomycin, two amino sugars are attached to strepidine.  In neomycin family, there are amino sugars attached to 2-deoxy streptamine. - The aminoglycoside antibiotics contain two important structural features. They are amino sugar portion and centrally placed hexose ring, which is either 2-deoxystreptamine or streptidine. 1. Amino sugar portion i. The bacterial inactivating enzymes targets C-6 and C-2 position and the substitution with methyl group at C-6 increases the enzyme resistance. ii. Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not affect the activity. 2. Centrally placed hexose ring (aminocyclitol ring) i. Various modifi cations at C-1 amino group have been tested. The acylation (e.g. amikacyn) and ethylation (e.g. 1-N-ethylsisomycin) though does not increase the activity helps to retain the antibacterial potency. ii. In sisomicin series, 2-hydroxylation and 5-deoxygenation result in the increased inhibition of bacterial inactivating enzyme systems. Thus, very few modifications of the central ring are possible, which do not violate the activity spectrum of aminoglycosides. Lecturer Notes_Dr. S. Mondal_B. Pharm 6th Semester_GITAM (Deemed to be University) Page | 4 E-mail: [email protected] View publication stats