chapter-1 introduction medicinal chemistry was...

Chapter-1 Introduction

Medicinal chemistry was defined by IUPAC as a chemistry-based discipline,

involving aspects of the biological, medical and pharmaceutical sciences. It is

concerned with the invention, discovery, design, identification and preparation of

biologically active compounds, the study of their metabolism, the interpretation of

their mode of action at the molecular level and the construction of structure-activity

relationships (SAR), which is the relationship between chemical structure and

pharmacological activity for a series of compounds.

Medicinal chemistry is central to modern drug discovery and development.

For most of the 20th

Century, the majority of drugs were discovered either by

identifying the active ingredient in traditional natural remedies by rational drug

design, or by serendipity. In 21st Century drug discovery has focused on drug targets

and high-throughput screening of drug hits and computer assessed drug design to fill

its drug pipeline. Medicinal chemistry has advanced during the past several decades

from not only synthesizing new compounds but to understanding the molecular basis

of a disease and its control, identifying biomolecular targets implicated as disease-

causing and ultimately inventing specific compounds (called ''hits'') that block the

biomolecules from progressing to an illness or stop the disease in its tracks. Medicinal

chemists use structure-activity relationships to improve the ''hits'' into 'lead candidates'

by optimizing their selectivity against the specific target, reducing drug activity

against non-targets and ensuring appropriate pharmacokinetic properties involving

drug distribution and clearance1.

The roots of medicinal chemistry lie in many branches of chemistry and

biology. Pharmaceutical chemistry reflected the fact that some nineteenth century

pharmacists, working in their apothecary laboratories, were the first to extract and

purify naturally occurring drugs. Some of the tasks of medicinal chemistry were

claimed by biological sciences. In 1876 the pharmacologist Buchheim wrote that "the

mission of pharmacology was to establish the active substances within the [natural]

drugs, to find the chemical properties responsible for their action and to prepare

synthetically drugs that were more effective".When pharmacologists became

preoccupied with other objectives, ―to study the change brought about by the drug in

the organism and then to explore the possible influence of such changes upon

pathological conditions", chemists took over the isolation and chemical identification

of natural plant constituents with a background of medical folklore. They also


embarked on the synthesis of structural analogs of such prototype compounds with

potential therapeutic activity. Gradually this led to searches for new "lead" structures

by screening synthetic organic compounds with or without relationships to naturally

occurring drugs. As ever increasing numbers of biologically active substances became

known, it was found that synthetic chemicals often produced effects that were more

useful medicinally than those attributed to natural materials, perhaps because plant

metabolites are not usually intended by nature to be of therapeutic value in animal

systems.

Comparisons of chemical structures with trends in biological behavior

stimulated the formulation of hypotheses on mechanisms of drug action at the turn of

the present century. Drug design has also been aided by the increasing understanding

of biochemical metabolism and biosynthesis, and by statistical analysis of some

relationships of physical properties of chemicals and their biological performance.

This progress has begun to erode the randomness of medicinal chemistry to a science

in its own right2.

The discipline of medicinal chemistry is devoted to the discovery and

development of new agents for treating diseases. Most of this activity is directed to

new natural or synthetic organic compounds. Inorganic compounds continue to be

important in therapy, e.g. trace elements in nutritional therapy, antacids and

radiopharmaceuticals, but organic molecules with increasingly specific

pharmacological activities are clearly dominant. Development of organic compounds

has grown beyond traditional synthetic methods. It now includes the exciting new

field of biotechnology using the cell's biochemistry to synthesize new compounds.

Techniques ranging from recombinant DNA and site-directed mutagenesis to fusion

of cell lines have greatly broadened the possibilities for new entities that treat disease.

The pharmacist now dispenses modified human insulins that provide more convenient

dosing schedules, cell-stimulating factors that have changed the dosing regimens for

chemotherapy, humanized monoclonal antibodies that target specific tissues and fused

receptors that intercept immune cell-generated cytokines3.

Medicinal Chemistry Covers the Following Stages:

In the first stage new active substances or drugs are identified and prepared from

natural sources, organic chemical reactions or biotechnological processes. They are

known as lead molecules. The second stage is optimization of lead structure to


improve potency, selectivity and lessen toxicity. Third stage is development stage

which involves optimization of synthetic route for bulk production and modification

of pharmacokinetic and pharmaceutical properties of active substance to render it

chemically useful.

Medicinal chemistry is the application of chemical research techniques to the

synthesis of pharmaceuticals. During the early stages of medicinal chemistry

development, scientists were primarily concerned with the isolation of medicinal

agents found in plants. Today scientists in this field are also equally concerned with

the creation of new synthetic drug compounds. Medicinal chemistry is almost always

geared towards drug discovery and development.

Medicinal chemists apply their chemistry training to the process of

synthesizing new pharmaceuticals. They also work on improving the process by

which other pharmaceuticals are made. Most chemists work with a team of scientists

from different disciplines, including biologists, toxicologists, pharmacologists,

theoretical chemists, microbiologists, and bio-pharmacists. Together this team uses

sophisticated analytical techniques to synthesize and test new drug products and to

develop the cost effective and environmentally friendly means of production.

The focus on development of new synthetic drug compounds has resulted in

the incorporation of many other disciplines, such as biochemistry and molecular

biology into medicinal chemistry. These areas include biology, computer aided

design, X-ray crystallography, metabolism and pharmacokinetics, legal and regulatory

affairs, clinical franchise management, pharmaceutics and process research

chemistry4.


Molecular Pharmacology

Hundreds of thousands of new organic chemicals are prepared annually throughout

the world and many of them are entered into pharmacological screens to determine

whether they have useful biological activity. This process of random screening has

been considered inefficient but it has resulted in the identification of new lead

compounds whose structures have been optimized to produce clinical agents.

Sometimes a lead develops by careful observation of the pharmacological behavior of

an existing drug. The discovery that amantadine protects and treats early influenza

came from a general screen for antiviral agents. The use of amantadine in long term

care facilities showed that it also could be used to treat parkinsonian disorders. More

recently automated high-throughput screening systems utilizing cell culture systems

with linked enzyme assays and receptor molecules derived from gene cloning have

greatly increased the efficiency of random screening. It is now practical to screen

enormous libraries of peptides and nucleic acids obtained from combinatorial

chemistry procedures.

The techniques of molecular graphics and computational chemistry have

provided novel chemical structures that have led to new drugs with potent medicinal

activities3.

Medicinal

Chemistry

Pharmacognosy

Analytical Chemistry

NMR Spectroscopy

X-Ray Crystallography

Molecular Modeling

Combinatorial Chemistry

Microbiology

Pharmacology

Organic Chemistry

Physical Chemistry

Bio-Chemistry

Computational

Chemistry

Bioinformatics

Genomics/Proteomics

Immunology


Importance of triazene compounds

Cancer is a prevalent cause of death worldwide. Everyyear, several natural and

synthetic compounds are tested for various anti-cancer activities. Medicinal chemistry

deals with synthesis of new agents for treating cancer by higher selectivity and lower

side effects5. Triazene compounds are a group of antitumour alkylating agents.

Dacarbazine (DTIC) and Temozolomide (TMZ)6-7

are two members of triazenes used

in the clinical treatment of metastatic melanomas, soft tissue sarcoma, Hodgkin’s and

non-Hodgkin’s lymphoma. Studies show that the antitumour activities of the desired

drugs are dependent on three adjacent nitrogen atoms8-12

. Due to lipophylic character

of temozolomide, it is capable to cross the blood-brain barrier. For this reason it is

the first line therapeutic option in the treatment of primary and metastatic brain

tumours13-14

.

The other well-known diaryltriazene derivative is diminazene aceturate (Berenil), the

salt of 1,3-bis(4-amidinophenyl)triazene. Its capacity to bind to DNA has been

recognized very early15

. The binding to DNA occurs via complexation into the minor

groove of AT-rich domains of DNA double helices. Diminazene aceturate can also

bind to RNA and to DNA duplexes, exhibiting characteristic properties of both

intercalation as well as minor groove binding16

. Diminazene aceturate can act as

antiviral compound17

but has been mainly used as an anti-trypanosomal drug18-20

.

Aromatic triazenes are well known and have been widely studied due to their

important antitumour effects and low toxicity21-24

. In recent years this class of

compounds has received attention in a search for potential HIV-1 inhibitors25

.

Triazenes act as chemotherapeutic agents for many tumours such as brain, leukemia,

melanoma lymphoma and sarcoma26-30

. DTIC –an FDA- approved pro-drug activated

by N-demethylation in liver microsomes (microsomal enzyme CYP450) is the most

active single agent and thus considered a reference drug31-32

.

Triazenes have been used as protecting group in natural product synthesis33

and

combinatorial chemistry34

, ligands for organometallic catalysts35

, incorporated into

polymer36

and oligomer37

synthesis and used to prepare some heterocycles38

. More

recently, triazenes have been used to fascinate coupling of functionalized arenes to


passivated Si surfaces for applications in semiconductors and nanoelectronics39

.

Hydroxytriazenes have recently attracted attention due to a variety of interesting

application including complexometric40

and spectrophotometric determination of

transition metals41

, antibacterial42-43

, antifungal43

, anti-inflammatory44

, insecticidal45

,

wound healing46

, analgesic agents47

and use as photolabile reagents for synthesis of

azodyes48

.

Triazene compounds* as potential antitumour drugs

1. Market Opportunity

Today there are ― smart ‖ drugs on the market that target tumour specific molecules.

In spite of that, most of the tumour patients are still treated with classical

chemotherapeutics. Since the main obstacle for the success of such standard therapy is

the development of tumour cell resistance, a combination of 2-3 cytostatics is applied

to increase the efficiency and reduce the possibility of resistant development.

Sales of the world’s best selling cytostatic is increasing annually on a regular basis

and currently exceeds 5 billion dollar per year. Platinol (cisplatin), the most frequently

used classical cytostatic has the annual sales worth over 100 million dollar.

Tumour cell micrograph taken with scanning electron microscope.

* - Google Search


2. Innovation description

Because of cross- resistance development to classical cytostatics, new compounds that

target tumour cells via different mechanism than classical cytostatics would be very

welcome.

Triazene analogues described in this offer their pharmaceutically acceptable

salts and N-acyl derivatives have several important characteristics.

They show cytotoxicity in very low concentrations.

They show good solubility.

Mechanism of action does not involve binding to DNA i.e. it does not affect

DNA.

Parental tumour cells as well as their sub-lines resistant to classical cytostatics

like cisplatin, vincristine and methotrexate show high sensitivity to mentioned

compounds.

Normal cells show less sensitivity to the same compounds.

Due to mentioned advantages triazene compounds can be used as active substances in

various pharmaceutical preparations for tumour treatment either as a single drug or in

combination with other cytostatics.


For the study of an open chain nitrogen compounds like triazene; the

triazene is obtained by the replacement of protons in primary and secondary

aromatic and aliphatic amines by arenediazonium ions49-50

.

Originally the triazenes were known as the diazoamino compounds, but in

the present IUPAC nomenclature51

that term may be used only for a special

group of triazenes viz HN=N—NH2 . In such reaction (1) derivatives of the

triazene of the type

obtained.

Where R = alkyl, aryl or Heteroaryl

R' = H, alkyl, aryl or Heteroaryl

The triazenes were probably first discovered by P.Griess52

. 1, 3-

diphenyltriazene was synthesized from 3-aminobenzoic acid and nitrousfumes.

The 1, 3-diphenyltriazene and 1-phenyl-3-methyltriazene were isolated53-55

.

Mono substituted triazenes were prepared by reduction of an azide56

(2).


Generally, disubstituted triazenes were acidic and gave cuprous salts57

and

the 1-aryl-3,3-dialkyltriazenes gave stable picrates. Moreover, 1, 3-disubstituted

triazenes possessed following tautomerism structure but separate tautomers, yet not

identified (3).

It was found that some 1, 3-diaryltriazenes58-62

obtained in different forms.

Attempts to prepare isomeric 1, 3-diaryltriazenes gave the same product (4).

In alkaline solution, disubstituted triazenes63

were alkylated and the isomeric

products shown below detected from the reaction (5).


The common acylating agents when acted on mono and disubstituted triazenes

gave monoacyl derivatives64-66

.

Diazonium salts when reacted with disubstituted triazenes gave

pentazadienes67-68

.

Oxidation of disubstituted triazenes with potassium permanganate gave

Hexazadienes69

(6).

Triazenes were prepared either by the coupling of diazoniumsalts with primary

or secondary amines70

(7) or by the reaction of azides with Grignard reagents71-72

(8).


Disubstituted hydroxytriazenes R—N=N—N(OH)R, were known in

literature73

. Generally, hydroxytriazenes were crystalline solids, acidic enough to

dissolve in aqueous alkali.

Disubstituted hydroxytriazenes were decomposed by strong acid in to

diazoniumsalts74-75

(9).

Reduction of disubstituted hydroxytriazenes with aluminium amalgam gave

disubstituted triazenes76

(10).

The salts of hydroxytriazenes when reacted with alkylhalides gave alkyl

derivatives77

.

1-p-nitrophenyl-3-methyl-3-methoxytriazene was synthesized from O, N-

dimethylhydroxylamine and p-nitrobenzenediazonium chloride (11a).


Moreover, hydroxytriazene possessed tautomerism with the triazene-N-oxide

structure (11b).

Hydroxytriazenes and triazeneoxides were prepared by coupling of diazonium

salts with hydroxylamines78

(12, 13, 14).


The reaction of nitrosobenzenes with arylhydrazines gave

diarylhydroxytriazenes79

(15). Whereas N-aryl-N-alkylhydrazines gave with difficulty

hydroxytriazenes or triazene oxides79

.

Monosubstituted hydroxytriazenes80

on treatment with dilute H2SO4 gave

azides (16).


A reaction of benzotriazine oxides with alkali gave hydroxytriazene80

(17).

Sulfonyltriazene oxides were prepared from the reaction of nitrosobenzenes

with N, N '- dibenzenesulfonylhydrazine in the presence of alkali81

(18).

The triazene oxide was obtained from the reaction of nitric acid and

secondary amines82

.

Dimroth83

obtained triazenes by the action of Grignard reagent on alkyl or

arylazides (19).


Where R and R' = alkyl or aryl

1–phenyltriazene56

was synthesized by reduction of phenylazide with

stannous chloride in suitable solvent.

Wiberg and Pracht84

and Fanghanel85-86

discovered Stereoisomeric

triazenes.

Preussmann87

have shown 1-aryl-3,3-dialkyltriazenes as potent carcinogens as

well as antitumour compound.

Sieh88

obtained 1–benzyl–3–n–butyltriazene from butyllithium in pentane

and benzylazide.

Scaiano89

observed equilibrium mixture of tautomers of 1,3-diphenyltriazene

in methanol as solvent by using Flash photolysis, transient spectroscopy and laser

induced optoacoustic calorimetry (LIOAC).

Lippert90

showed that the π– electron distribution in 1–aryl–3,3-dialkyltriazene

possessed 1, 3 dipolar mesomeric structure.

Ahern91

established monoalkyltriazenes undergo degradation in aqueous

solution to gave mixtures of triazenes, arylamines and 1, 3-diaryltriazenes.


Triazenes of type Ar—N=N—NHCH2Y92-93

(where Y electron withdrawing

group) were prepared from reaction of the diazonium salts and the α – substituted

alkylamines.

The reaction between diazotized anthranilate esters and alkylamines gave

unstable 1-alkyl-3(o-carbalkoxyphenyl)-triazenes94

.

The 3-aryl-triazene-1-oxides95

were useful for treating inflammatory diseases.

1-aryl-3-alkyl-3-hydroxymethyltriazenes96-97

were prepared by the action of

diazonium salts on the mixture of methylamine and formaldehyde.

Five-membered and six-membered heterocycles were synthesized from 1-(2'-

acetylphenyl)-3-alkyltriazenes by Keith Vaughan98

, et al.

The series of 4-hydroxyl-3,4-dihydro-1, 2, 3-benzotriazines were synthesized

and showed as antitumour compounds by Ronald J. Lafrance99

, et al.

1-aryl-3-arylthiomethyl-3-methyltriazenes and 3-(arylazo)-1,3-thiazolidines

were synthesized by Keith Vaughan100

, et al.

The series of 1–aryl–3–aryloxymethyl–3–methyltriazenes were synthesized by

the reaction of the acetoxymethyltriazene with the appropriate phenol in dry

chloroform solution by M. P. Merrin101

, et al.

The series of 3-aryl-1-methyltriazene 1-oxides were synthesized by Lynn M.

Cameron102

, et al.

A novel photosensitive triazene polymer were synthesized and characterized

by Jurgen Stebani103

, et al.

The anticancer triazene compounds were synthesized by Emilia Carvalho104

,

et al.

The synthesis and plasma hydrolysis of acyloxymethylcarbamate derivatives

used as antitumour triazenes by Emilia Carvalho105

, et al.


A new and simple synthesis of N–Succinimidyl-4-[triazene derivatives]

iodobenzoate studied by Ali Khalaj106

, et al.

The synthesis and antimicrobial studies of hydroxytriazenes were reported

by Ajay K. Goswami107

, et al.

The anti-inflammatory compounds of sulfoaryl 3,3–disubstituted triazenes

were synthesized by M. Kazemekaite108

, et al.

The polymer supported triazenes were synthesized by Bernhard Erb109

, et

al.

The new strategy for synthesis of polymeric supports with triazene linkers

by Ryszard Lazny110

, et al.

The synthesis of triazene from the reaction of imidazol-2-ylidenes with azides

reported by Dinitri M. Khramov111

, et al.

The aromatic fluorination by decomposition of triazenes in ionic liquids

studied by Chan – Kook Chu112

, et al.

3-hydroxy-3-phenyl-1-o-trifluorophenyltriazene was synthesized and reported

as a selective complexing ligand for the extraction spectrophotometric determination

of Ni+2

ions113

.

The synthesis and primary cytotoxicity evaluation of new diaryltriazenes

reported by S Unsalan and S Rollas114

, et al.

The synthesis and antineoplastic activity of certain triazene and triazeno

acridine combilexin derivatives by Samir M. El-Moghazy Aly115

, et al.

The synthesis and crystal structure of a 1,3–bis(2-cyanophenyl)triazene as

hydrogen bonded compound reported by Mohammad R. Melardi116

, et al.

The anti-inflammatory compounds of hydroxytriazenes and their vanadium

complexes were synthesized by Kalpana Singh117

, et al.

3-hydroxytriazenes used as corrosion inhibitors for brass in ammoniacal

environment were synthesized by S. Kumar118

, et al.


The antiviral and cytotoxic activities of aminoarylazo compounds and

aryltriazene derivatives were synthesized by Michele Tonelli119

, et al.

The anti-inflammatory compounds of hydroxytriazenes derivatives were

prepared by L. S. Chauhan120

, et al.

The hydroxytriazenes compounds were synthesized and their wound

healing activity studied by L. S. Chauhan121

, et al.

The synthesis and antimicrobial activity of some substituted

hydroxytriazenes were reported by L. S. Chauhan122

, et al.

The hydroxytriazenes as analgesic compounds were synthesized by L. S.

Chauhan123

, et al.

The complexometric determination of Zn (II) in pharmaceutical samples

using hydroxytriazenes by khanam R.124

, et al.

The electrochemical behaviour and antifungal activity of complex of cu (II)

with 3-hydroxyl-3-m–tolyl-1-p-(sulphonamido)phenyltriazene was studied by P.

Joshi125

, et al.

The synthesis, DNA Cleavage studies, cytotoxicity study and antibacterial

activity reported by Vanessa O. Domingues126

, et al.

The synthesis of antitumour phosphanylidene Stannayl triazole and triazene

compounds reported by Soher S. Maigali127

, et al.

The synthesis and insecticidal hydroxytriazenes were reported by O.

Ombaka128

, et al.

The series of novel triazene derivatives were synthesized from sulfonamides

by Seda Unsalan129

, et al.

The synthesis and biological evaluation of 4-nitro-substituted-1,3-

diaryltriazenes as potent antitumour agents reported by Tamara Cimbora– Zovko130

,

et al.


Some new class of hydroxytriazenes were synthesized, characterized and

their biological activity studied by Prabhat Kumar Baroliya131

, et al.

The antibacterial and antifungal compounds of hydroxytriazenes were

synthesized by A. O. Ombaka132

, et al.

The synthesis, activity prediction and spectrophotometric study of

molybdenum complex of 3–hydroxy–3–p–tolyl–1–p–carboxyphenyltriazene reported

by Babel- Tushita133

, et al.

The antibiotic compounds of hydroxytriazene with copper (II) complexes

were reported by Ajay k. Goswami134

, et al.

The antifungal activity of hydroxytriazenes, schiffs base and their ternary

complexes of zinc (II) were reported by Dr. N. S. Chundawat135

, et al.

The amphiphilic block copolymer containing triazene moieties were

synthesized and their fluorescence property showed by Emil C Buruiana136

, et al.

The new triazene monomer was synthesized and employed as a crosslinking

agent partner with epoxy matrix using ethyl methyl imidazole as a curing agent in

order to investigate the effect of triazene moieties on polymeric properties for laser

ablation application by Archana S. Patole137

, et al.

The spectrophotometric studies and application of a triazene ligand for solid

phase extraction of ultratrace copper were reported by Mahmood Payehghadr138

, et

al.

Hadi Adibi139

, et al; discovered the compounds containing triazene ring

structure are cytotoxic agents and clinically used as antitumour alkylating agents

and a series of triazene derivatives holding alkyl and aryl moieties were synthesized

and proved to be potent cytotoxic agents in-vitro against human cancer cell lines

and a non cancerous cell line.

The 3-hydroxy-3-isopropyl-1-(4-sulphonamidophenyl)triazene was

synthesized and analytically used for spectrophotometric determination of nickel

(II) studied by Rehana Khanam140

, et al.


The structural and biocidal studies of organotin(IV) complexes of triazene-1-

oxides were studied by R. Sharma141

, et al.

The biological activities of hydroxytriazenes and their nickel complex were

reported by Kodli KK142

, et al.

The biological activities of hydroxytriazenes and their iron complexes were

reported by N. K. Choubisa143

, et al.

The synthesis and antimicrobial studies of some sulfonato (sodium salt) based

hydroxytriazenes and their cobalt(II) complexes were reported by Dr. G. P. Singh144

,

et al.

The antibacterial activity of hydroxytriazenes, schiff’s base and their ternary

complexes of zinc(II) with schiff’s base and hydroxytriazenes were reported by N. S.

Chundawat145

, et al.


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World Journal of Pharmacy and Pharmaceutical Sciences, Vo1.4, Issue 02,

330-335 (2015).

chapter-1 introduction medicinal chemistry was...

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