Introduction

Medicinal chemistry is a specialised science that has evolved to encompass a

broad range of disciplines, especially synthetic organic
chemistry, pharmacology and various other biological specialties concerned with
the identification, design, chemical synthesis and development of bioactive
compounds or pharmaceutical agents (drugs) for therapeutic use. It involves the
application of a number of specialized disciplinary approaches all focused on the
ultimate goal of drug discovery.

Structure Activity Relationships (SAR) refers to the relations between the

molecular structure and biological or physiochemical activity of drugs. The
analysis of SAR enables the determination of the chemical groups or moieties
responsible for eliciting a biological effect. This allows modifications of the effect
of a drug (for instance, to improve the activity or reduce the toxicity of a drug) by
changing its chemical structure appropriately.

Chemical class of drug- Aminoglycosides (Antibiotics)

Aminoglycosides are bactericidal antibiotics which interfere with the ribosomal

functions (30s ribosomal unit) and inhibit the protein synthesis of bacteria. The
first aminoglycoside found, streptomycin, was isolated from Streptomyces
griseus in the year 1944. They can be classified based on the source:

1. From genera Streptomyces (suffix-mycin) Streptomycin, Neomycin,

Kanamycin, Paromomycin, Tobramycin, Spectinomycin.
2. From genera Micromonospora (suffix-micin) Gentamicin, Sisomicin
3. Semisynthetic derivatives Amikacin, Netilmicin, Dibekacin, Isepamicin,
Arbekacin

Aminoglycosides are so named because their structures consist of aminosugars

joined to an aminocyclitol (a non-sugar) by a glycosidic bond. In majority of
aminoglycosides, the aminocyclitol moiety is 2-deoxystreptamine which is placed
centrally between 2 aminosugars as shown below

Aminosugar -O- 2-deoxystreptamine -O- Aminosugar

However, in streptomycin, the aminocyclitol is streptidine which is not placed

centrally, rather, it is placed laterally to the aminosugar (streptose), which in
turn is joined to another aminosugar (N-methyl-L-glucosamine).
 Streptidine -O- Streptose aminosugar -O- N-methyl-L-glucosamine
aminosugar

Mechanism of microbial resistance to aminoglycosides

The irrational use of aminoglycosides has resulted in the development of

resistant bacterial strains. These resistant strains inactivate the aminoglycosides
by synthesizing enzymes capable of acetylating, phosphorylating, or adenylating
key amino or hydroxyl groups of aminoglycosides. The following constitute the
bacterial inactivating enzymes-

Amino-acetyl transferases (AAC) - Acetylate the 6-NH 2 or 2-NH2 of ring I,

3-NH2 of ring II
O-Phosphotransferases (APH) - Phosphorylate the 3-OH of ring I or 2-OH
of ring III
Nucleotidyl transferases (ANT) - Adenylate the 4-OH of ring I, 2-OH or 4-
OH of ring III

Structure Activity Relationships (SAR)

 Ring I- It is crucially important for characteristic broad spectrum
antibacterial activity.
Ring II- Few modifications of ring II functional groups are possible without
appreciable loss of activity in most of the aminoglycosides.
Ring III- Functional groups of ring III appear to be somewhat less sensitive
to structural changes than those of either ring I or ring II.
Aminoglycosides are usually composed of 3 rings but sometimes they may
have 4 rings (eg,paromomycin) .

Ring I

The substituent at position 6 of ring I and the number of protonated

amino groups of ring I are important structural characteristics responsible
for interaction of aminoglycosides with rRNA of 30s subunit.
Kanamycin B with amino groups at 6 and 2 positions is more active than
kanamycin A with 6-amino group and 2-hydroxyl group which in turn is
more active than kanamycin C with 6-hydroxyl group and 2-hy droxyl
group. [Kanamycin B > Kanamycin A > Kanamycin C].

R R
Kanamycin A -OH -NH2
Kanamycin B -NH2 -NH2
Kanamycin C -NH2 -OH
 Ring I is the primary target for the bacterial inactivating enzymes (AAC,
APH, ANT).
Methylation at either the 6-carbon or the 6-NH 2 positions confers
resistance to the enzymatic acetylation of 6-NH 2 group by AAC without
lowering the antibacterial activity. Eg. Gentamicin C1

Removal of 3-OH or the 4-OH or both in kanamycins confers

resistance to APH. Eg. Dibekacin

Since gentamicins, sisomicin and netilmicin lack hydroxyl group at 3

and 4 positions, they are not inactivated by APH.
1. Eg. Gentamicin [C1: R=R=CH3; C1a: R=R=H; C2: R=H, R= CH3]

2. Eg. Sisomicin
Ring II

The linkage between the sugar rings and the central ring II
(deoxystreptamine moiety) is an important structural characteristic
responsible for interaction of aminoglycosides with rRNA of 30s subunit.
The 1-NH2 group of kanamycin A can be acylated (eg, amikacin) with
activity largely retained. This modification of aminoglycosides has been
the best approach to regain bactericidal efficiency of this class of
antibiotics against resistant bacterial strains. CORRECTION: 1-NH2 is
not the one that is highlighted in the picture. It is the other NH 2
group in ring II.

Eg. Amikacin B

Similarly, netilmicin (R=-C2H5 )retains antibacterial potency of sisomicin

(R=H) and is resistant to several additional bacterial inactivating enzymes.
 In majority of aminoglycosides, the aminocyclitol moiety is 2-
deoxystreptamine which is placed centrally between 2 aminosugars (eg
sisomicin). In streptomycin, the aminocyclitol is streptidine which is not
placed centrally, rather, it is placed laterally to the aminosugar
(streptose), which in turn is joined to another aminosugar (N-methyl-L-
glucosamine)

Eg. Streptomycin-

Sisomicin-
Ring III

The 3-NH2 can be primary (Kanamycin A) or secondary (eg, Netilmicin)

with high antibacterial potency.

Netilmicin

Kanamycin
A

The antibacterial activity decreases with change in the functional group at

2 position in the following order- NH 2 (eg, seldomycin 5) > -OH (eg,
sisomicin) > H (2 deoxygentamicin).
 Seldomycin 5

Sisomicin

Gentamicins are resistant to ANT whereas kanamycins are not. This is

because this enzyme can adenylate the secondary equatorial 4-OH of
kanamycin but not the tertiary axial 4-OH of gentamicins.
Stereochemistry related factors will help aminoglycosides overcome
inactivation by bacterial enzymes.

Kanamycin
 Gentamicin

Conclusion

Therefore, it can be understood that the inactivating effect of bacterial enzymes

on aminoglycosides can be overcome by modifying the vulnerable functional
groups and applying certain chemical principles like the following-

If the target functional group is absent in a position of the structure

normally attacked by the inactivating enzyme, then the antibiotic will be
resistant to the enzyme. (eg, sisomicin).
Steric factors may confer resistance against bacterial inactivating
enzymes. (eg, gentamicins).
Conversion of primary amine to secondary amino group may confer
resistant to acetylation by AAC (eg, netilmicin).
Acylation of 1-NH2 by a bulky group (eg, amikacin) will help overcome
inactivation by AAC,ANT and APH.

References

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Organic Medicinal and Pharmaceutical Chemistry, Lippincott Williams &
Wilkins, USA.
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kanamycin prevents significant loss of activity in resistant bacterial
strains, Organic and Biomolecular Chemistry, vol. 14, no. 2, pp. 516-525.
Available from:
 http://pubs.rsc.org/en/content/articlelanding/2016/ob/c5ob01599e#!
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http://www.nature.com/ja/journal/v59/n9/abs/ja200673a.html [25
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