Download SUMMARY The present thesis entitled “Synthesis of some

SUMMARY
The present thesis entitled “Synthesis of some thiocarbamide and thiohydantoin derivatives with their Antithyroid
functions”, has been completed under the inspiring guidance of Dr. T.P. Agarwal, Reader and Head of department of Chemistry,
K.G.K. College, Moradabad.
The thesis is divided into starting with general introduction and four sections as Sec. A, Sec. B, Sec. C & Sec. D.
The present work contains the chemistry and application of highly interesting and significantly useful organic sulphur and
Nitrozen compounds. Present investigation include an uptodate summary of significant contributions appearing in the literature in this
field of medicinal chemistry and also summarizes the progress of work done during the course of this investigation.
Organic sulphur and Nitrozen compounds occupies a position of importance due to their remarkable pharmacological
activity. They contain a highly biologically active Skeleton, which is a considerable chemotherapeutic interest and systematic
researches with derivatives of these compounds have opened a new vistas in field of modern medicinal chemistry.
The thesis is divided in 4 main sections - A, B, C, & D. My humble contributions are given in these chapters.
Section ‘A’ entitled “Introduction” gives basic knowledge about Antithyroid compounds. Antithyroid compounds may be
broadly defined as chemical compounds that depress the thyroid function. They lower the metabolic rate by interfering with the
synthesis, release or peripheral action of thyroid hormone.
Antithyroid drug fall into 2 main groups to their mode of action, both groups are equally effective. The 1 st and most active
group includes the thiocarbamide derivatives. Such as thiourea, thiouracil and propyl thiouracil. The 2nd category contains compounds
that have an amino benzene ring in their structure, including sulphar drug, Para-aminobenzoic acid, Para-amino salicylic acid etc.
Other compounds such as 5-vinyl-2-thiooxazolidine from seed of cabbage, kale and turnips are also active goitrogens. The
sulphenylureas, a group of compounds used clinically in treatment of diabetes mellitus, also have antithyroid properties.
Antithyroid action is more pronounced is case of thiourea or thiouracil and its derivatives. The progress of research aimed
the obtaining effective and specific antithyroid agents, useful in the treatment of thyroid diseases could involve synthesis of analogues
of some well known antithyroid agents. A search for more active and least toxic substance led to the use of thiocarbamide type sulphur
compound. Cheymol and Coworkers studied the structure and function relationships of several thiohydantoins derivatives and found
that among thiohydantoins, 5:5-dimethyl dithiohydantoins possessed the greatest antithyroidal activity.
In brief, with few exceptions, the active antithyroid compounds are – (1) Compounds containing – NH-C=S grouping, (2)
Thiocyanates and
(3) Amino benzene or aminoheterocycles with a free amino group.
The investigations mainly consists of –
1.
2.
Synthesis and characterization of some thiocarbamide and thiohydantoin derivatives.
Pharmacological screening in thiocarbamide and thiohydantoin derivatives.
These compounds have been prepared with a view that they might prove to be antithyroid drug due to their facile oxidation
into cyclic derivatives.
The section – ‘B’ named “Thiocarbamide derivatives” is divided in 2 chapter. Chapter 1 is introduction about
thiocarbamide compounds. The main practical application has been in the treatment of hyperthyroidism, a disorder in which the
thyroid produces excessive amounts of its hormones. Various clinical reports show that thiocarbamides were found to be effective
drugs in thyroid diseases.
In chapter II of section ‘B’ named ‘Experimental’. There is the synthesis and preparation of some thiocarbamides and
amidino thiocarbamides with their elemental analysis shown in tables.
Section ‘C’ is titled “Thiohydantoin derivatives”. This section is divided into chapter 1 named “Introduction and
Experimental” describes about ureides and purine derivatives – like thiohydantoin. Here we synthesis some new types of
thiohydantoins derivatives which could exert effective antithyroid action. Identification of thiohydantoin compounds will be done by
various physical and chemical methods and their antithyroid properties will be evaluated. These studies have not been reported in
literature so far, and consequently, knowledge about their antithyroid activity may open a new vistas in the field of medicinal
chemistry.
In this chapter also there is the synthesis and preparation of various heterocyclic compounds and their derivatives, various
chloro acetylated derivatives with their experimental analysis. All the details have shown in tables.
In final section ‘D’ which is entitled as ‘Pharmacological Screening’, attempts have been made regarding antithyroid
activity and the pharmacological screening results of various compounds synthesized in the laboratory. In this last section we
summarize the final result and discussion about thiocarbamide derivatives and thiohydantoin derivatives.
Thiocarbamide Derivatives
N-aryl formamidino-{N-5(-4-chloro-phenyl) –1,3,4,-oxadiazol-2-yl} thiocarbamide hydrochloride, replacement of aryl
group with p-tolyl, p-anisyl caused the conversion of compound into antithyroid compound but the activity was much below than the
compound, with the activity of thiouracil.
In N-aryl formamidino –N-{5-(4-fluoro-phenyl)- 1, 3, 4, –oxadiazol-2-yl} thiocarbamide hydrochloride replacement of pchloro p-phenyl and p-anisyl converted the compound to thyroid stimulatory compound rather than antithyroid compound.
In N-aryl-formamidino-N-{5(-4-methoxy phenyl)- 1, 3, 4– thiodiazol-2-yl} thiocarbamide hydrochloride, the replacement
of aryl group by p-anisyl group caused the conversion of compound into antithyroid but the activity was much low as p-anisyl group
caused a stimulatory effect on thyroid.
In N-aryl formamidino-N-{4-(5-chloro phenyl) oxazol-2-yl} thiocarbamide hydrochloride, p-phenityl group showed
antithyroid activity but the activity was very low. Replacement of p-methyl group produced stimulatory effect on the thyroid.
In N-aryl formamidino – (N-naphthothiazol-2-yl) thiocarbamide hydrochloride, the replacement of aryl group by Omethoxy group showed antithyroid activity which is much less than the activity of well known reported drug thiouracil.
In N-aryl formamidino-N-(3-pyrid–2-yl) thiocarbamide hydrochloride, the replacement of aryl group with p-chloro phenyl,
p-phenityl, showed a stimulatory effect on the thyroid.
In N-aryl-formamidino –N-(4-pyrid-2-yl) thiocarbamide hydrochloride, the replacement of aryl group by p-tolyl and panisyl caused antithyroid activity which is not even 25% of the activity of reported drug thiouracil.
In compound N-aryl-formamidino-N (quinol-5-yl) thiocarbamide hydrochloride replacement of aryl group caused the
conversion of compound into an antithyroid compound to some extent and the activity was much low as compared to standard drug
thiouracil.
In compound N-aryl formamidino-N- (2-benzimidazol-2-yl) thiocarbamide hydrochloride, the replacement of aryl group by
p-tolyl group possibly converted the compound into thyroid stimulating agent rather than an antithyroid compound.
In compound N-aryl-formamidino-N-2-(4-nitro) Benzothiazolyl thiocarbamide hydrochloride, the replacement of aryl
group by p-phenityl group showed antithyroid activity which is not equivalent to one fourth of the activity of thiouracil.
In compound N-aryl-Formamidino-N-{2-Indazol-2-yl} thiocarbamide hydrochloride, the replacement of aryl group by
phenyl group caused goitrogenic activity and the activity was equivalent to thiouracil, a standard drug.
In compound N-aryl formamidino-N-(4-antipyrin-2-yl) thiocarbamide hydrochloride, the replacement of aryl group by ptolyl group does not show significant antithyroid activity.
Thiohydantoin derivatives
In N3 – thiazdyl thiohydantoin, the compound showed stimulatory effect on the thyroid.
In compound, N3 –(4-aryl-thiazolyl) thiohydantoin, the replacement of aryl group by phenyl group converted the
compound into active antithyroid agent and the activity was more than the activity of thiouracil and replacement of aryl group by pbromophenyl caused the conversion of compounds into an antithyroid compound but the activity was very much low.
In compound N3 –{4-(substituted) phenyl oxazolyl} thiohydantoin, the replacement of aryl group by p-methoxy group
caused stimulatory effect on the thyroid and possible conversion of compounds into thyroid stimulating agent.
In compound N3 –{5-(substituted) phenyl-1,3,4-oxadiazolyl} thiohydantoin, the replacement of aryl group by p-ethoxy
group caused the conversion of compound into an antithyroid agent upto some extent but the activity was not equivalent to 1½ of the
activity of thiouracil.
In compound N3 –{5(substituted) phenyl-1,3,4-thiadiazolyl} thiohydantoin, the replacement of aryl group with p-methoxy
group caused inhibitory effect on thyroid and also caused conversion of compounds as goitrogenic substance but the activity was low.
In compound N3 – {2-(substituted) benzothiazolyl} thiohydantoin, the replacement of aryl group with p-tolyl group caused
stimulatory effect on the thyroid and possibly conversion of compounds into thyroid stimulating agent.
The compound, N3 –(naphthothiazolyl) thiohydantoin, showed a thyroid stimulatory effect rather than antithyroid
compound.
The compound, N3 –(Pyridyl) thiohydantoin showed antithyroid activity but the activity was very low.
The compound, N3 –(pyrimidyl) thiohydantoin, showed active stimulatory effect on thyroid, instead of antithyroid
compound.
The compound N3 –(1,3-diphenyl pyrrazolyl) thiohydantoin caused inhibitory effect on the thyroid.
The compound N3 –(benzimidazolyl) thiohydantoin exhibited a stimulatory effect on the thyroid rather than antithyroid
compound.
The compound N3 – (indazolyl) thiohydantoin caused an inhibitory effect on the thyroid and the conversion of compound
as goitrogenic substance but the activity was very low
The compound N3 – (quinolyl) thiohydantoin caused stimulatory effect on the thyroid rather than antithyroid compound.
Research Scholar
(Km. Swati Pawar)