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1. Thiazole
Thiazole, or 1,3-thiazole is a unique heterocycle containing sulphur and nitrogen atoms, occupies
an important place in medicinal chemistry. It is an essential core scaffold present in many natural
(Vitamin B1- Thiamine) and synthetic medicinally important compounds. Synthetic drugs
belonging to the thiazole family consist of the antimicrobial acinitrazole and sulfathiazole,
antibiotic penicillin, antidepressant pramipexole, antineoplastic agents Bleomycin and Tiazofurin,
anti-HIV drug Ritonavir, the antiasthmatic drug cinalukast, antiulcer agent Nizatidine.
Additionally, extensively used thiazole derivatives are the non-steroidal immunomodulatory drug
Fanetizole, and anti-inflammatory drug Meloxicam. Thiazole derivatives with polyoxygenated
phenyl module have exhibited encouraging anti-fungal activity. Thiazoles found from microbial,
and marine ancestries reveal antitumor and antiviral activities. Thiazole is recognized as ligand of
estrogen receptors and also as unique kind of antagonists for adenosine receptors.
Thiazole is a clear to pale yellow liquid with a boiling point of 116-118oC. Its specific gravity is
1.2 and it is sparingly soluble in water. It is soluble in alcohol and ether. The odor of thiazole is
similar to pyridine. Thiazole is aromatic on the basis of delocalization of a lone pair of electrons
from the sulfur atom completing the needed 6 π electrons to satisfy Huckel’s rule. The resonance
forms are:
Thiazole chemistry has developed steadily after the pioneering work of Hofmann and Hantzsch.
Hantzsch thiazole synthesis is the interaction between a-haloketones or a-halogenoaldehydes and
thioamide. With proper choice of suitable reactants, thiazoles having alkyl, aryl or heterocyclic
substituents attached to any of the three positions (R1, R2 or R3) of the thiazole ring can be
synthesised.(Pola, 2016)

2. PRAMIPEXOLE
Mechanism of action
This is a nonergot dopamine agonists that is approved for the treatment of Parkinson’s disease.
Pramipexole is orally active agent. Pramipexole alleviates the motor deficits in patients who have
never taken levodopa and also in patients with advanced Parkinson’s disease who are treated with
levodopa. Dopamine agonists may delay the need to use levodopa in early Parkinson’s disease and
may decrease the dose of levodopa in advanced Parkinson’s disease. It has preferential affinity for
the D3 family of receptors. It is effective as monotherapy for mild Parkinsonism and is also helpful
in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing
out response fluctuations. Pramipexole may ameliorate affective symptoms.(Katzung.)
Structure-activity relationship of Pramipexole
PRAMIPEXOLE
Pramipexole is a tetrahydrobenzothiazole derivative, formulated as di-HCl salt (side chain NH and
hetero N) of pharmacologically-active single (S-(-)) isomer. It possesses neuroprotective effect
due to its ability to scavenge hydrogen peroxide and other free radicals and electrophiles.
Pharmacokinetics
Pramipexole is rapidly absorbed after oral administration, reaching peak plasma concentrations in
approximately 2 hours and is mainly excreted unchanged in the urine, and dosage adjustments are
needed in renal dysfunction. Cimetidine inhibits renal tubular secretion of organic bases and may
significantly increase the half-life of Pramipexole.(Whalen, Karen, 2013)
Advantages of Pramipexole:
Although nausea, hallucinations, insomnia, dizziness, constipation, and postural hypotension are
among the distressing side effects of Pramipexole, dyskinesias are less frequent than with

3. levodopa. Unlike the ergotamine derivatives (Bromocriptine, Pergolide), Pramipexole does not
exacerbate peripheral vascular disorders or cause fibrosis.
Bleomycin
Bleomycin is a mixture of metal-chelating glycopeptide antibiotics having potent antitumour
activity that cause scission of DNA by an oxidative process. It is isolated from Streptomyces
verticillius. Bleomycin naturally chelates copper ion but inside cells it chelates iron (II), produces
superoxide ions and intercalates between DNA strands—causes chain scission and inhibits repair.
It is highly effective in testicular tumour and squamous cell carcinoma of skin, oral cavity, head
and neck, genitourinary tract and esophagus; also useful in Hodgkin’s lymphoma.(Rang, Dale,
Ritter, Flower, & Henderson, 2012)
Mechanism of action
Bleomycin is most effective in the G2 phase of the cell cycle and mitosis, but it is also active
against non-dividing cells (i.e. cells in the G0 phase). It is often used to treat germline cancer. It
degrades preformed DNA, causing chain fragmentation and release of free bases. This action is
thought to involve chelation of ferrous iron and interaction with oxygen. A DNA–bleomycin–Fe2+
complex appears to undergo oxidation to bleomycin–Fe3+. The liberated electrons react with
oxygen to form superoxide or hydroxyl radicals, which, in turn, attack the phosphodiester bonds
of DNA, resulting in strand breakage and chromosomal aberrations. (Whalen, Karen, 2013)
BLEOMYCIN a ternary complex with molecular oxygen
N N
H2N
NH
O
H2N
NH2
OH2N
O
N
O NH
NH
N
NH
HN
HO
O
OH
O
N S
N
S
HN
O
R
Bleomycine A: R = S(CH3)3
Bleomycibe B:
NH2
H
N-CH2
NH2
O
O
OH
OH
HO
O
OH
OH
OH O
NH2
DNA binding
Interact heterocycl. bases
Electrostat. interact. with phosphates
N N
H2N
N
O
H2N
NH
OH2N
O
N
NH
NFe
O2

4. https://youtu.be/QZeEnbH_bR4
This animation consists of three parts, 1) the first is a simple backdrop that shows DNA and the
drug in the nucleus environment focusing on the areas of interest. 2) The second consists of
Bleomycin intercalating into DNA, the bisthiazole tail inserts into the helix area and then is
positioned to produce free hydroxyl radicals. 3) The final segment shows how the drug in the
presence of ferric ion and oxygen undergoes a dynamic action to form extremely reactive hydroxyl
radical in situ and degrade the sugar structure of DNA. This action results in loss of genetic
information necessary for DNA replication in cancer cells (and some normal cells!).
Structure-activity relationship of Bleomycin
Bleomycin binds Fe through multiple interactions with the amino terminal end of the peptide chain.
Interaction with DNA subsequently occurs through the bithiazole portion of the molecule, which
intercalates between G-C base pairs with a preference for genes undergoing transcription. Held in
proximity to DNA by this interaction, in an aerobic environment, Fe+2 is oxidized to Fe+3 in a
one-electron process with the electron being transferred to molecular oxygen. This gives the
activated form of bleomycin, which has been formulated as HOO~Fe(III)-bleomycin, which is a
ternary complex. NMR studies of bleomycin complexed with cobalt have confirmed the
intercalation of the bithiazole with adjacent G-C base pairs with the dimethylsulfonium chain

5. (bleomycin A2) projecting into the major groove where the sulfonium cation may interact with the
phosphate backbone.
The sugar moieties in the structure contributes to the water solubility and cell permeability of
bleomycin.(Strekowski et al., 1991)
Resistance: Although the mechanisms of resistance have not been elucidated, increased levels of
bleomycin hydrolase (or deaminase), glutathione S-transferase, and possibly, increased efflux of
the drug have been implicated. DNA repair also may contribute.
Pharmacokinetics: Bleomycin is administered by a number of routes. The bleomycin-inactivating
enzyme (a hydrolase) is high in a number of tissues (for example, liver and spleen) but is low in
the lung and is absent in skin (accounting for the drug’s toxicity in those tissues). Most of the
parent drug is excreted unchanged in the urine, necessitating dose adjustment in patients with renal
failure.
Adverse effects: Pulmonary toxicity is the most serious adverse effect of bleomycin, which occurs
in 10% of patients treated and is reported to be fatal in 1%. The pulmonary fibrosis that is caused
by bleomycin is often referred as “bleomycin lung.” In contrast to most anticancer drugs,
bleomycin causes little myelosuppression. Allergic reactions can also occur. About half the

6. patients manifest mucocutaneous reactions (the palms are frequently affected), and many develop
hyperpyrexia.(Rang, Dale, Ritter, Flower, & Henderson, 2012)
References
Katzung, B. G. S. B. M. A. (n.d.). Basic & Clinical Pharmacology.
Pola, S. (2016). Significance of Thiazole-based Heterocycles for Bioactive Systems. In Scope of
Selective Heterocycles from Organic and Pharmaceutical Perspective. InTech.
https://doi.org/10.5772/62077
Rang, H., Dale, M., Ritter, M., Flower, R., & Henderson, G. . (2012). Hyde, M. Rang and Dale’s
Pharmacology. Rang and Dale’s Pharmacology. https://doi.org/0443069115
Strekowski, L., Wilson, W. D., Mokrosz, J. L., Mokrosz, M. J., Harden, D. B., Tanious, F. A., …
Crow, S. A. (1991). Quantitative structure-activity relationship analysis of cation-
substituted polyaromatic compounds as potentiators (amplifiers) of bleomycin-mediated
degradation of DNA. Journal of Medicinal Chemistry, 34(2), 580–588.
https://doi.org/10.1021/jm00106a017
Whalen, Karen, R. F. A. P. (2013). Lippincott Illustrated Reviews: Pharmacology. Journal of
Chemical Information and Modeling (Vol. 53).
https://doi.org/10.1017/CBO9781107415324.004