Hetero Cyclic Compounds

Heterocyclic Compound

Introduction

Compounds classified as heterocyclic probably constitute the largest and most varied

family of organic compounds. After all, every carbocyclic compound, regardless of

structure and functionality, may in principle be converted into a collection of heterocyclic

analogs by replacing one or more of the ring carbon atoms with a different element. Even

if we restrict our consideration to oxygen, nitrogen and sulfur (the most common

heterocyclic elements), the permutations and combinations of such a replacement are

numerous

Heterocyclic compounds are organic compounds that contain a ring structure

containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as part of the

ring.[1] They may be either simple aromatic rings or non-aromatic rings. Some examples

are pyridine (C5H5N), pyrimidine (C4H4N2) and dioxane (C4H8O2).

Note that compounds such as cyclopropane, an anaesthetic with explosive properties, and

cyclohexane, a solvent, are not heterocyclic; they are merely cycloalkanes. The prefix

'cyclic' implies a ring structure, whereas 'hetero' refers to an atom other than carbon, as

above. Many heterocyclic compounds, including some amines, are carcinogenic.

Heterocyclic chemistry is the chemistry branch dealing exclusively with synthesis,

properties, and applications of heterocyles.

Nomenclature

Devising a systematic nomenclature system for heterocyclic compounds presented a formidable

challenge, which has not been uniformly concluded. Many heterocycles, especially amines, were

identified early on, and received trivial names which are still preferred. Some monocyclic

compounds of this kind are shown in the following chart, with the common (trivial) name in bold

and a systematic name based on the Hantzsch-Widman system given beneath it in blue. The rules

for using this system will be given later. For most students, learning these common names will

provide an adequate nomenclature background.

G.V.S.P JAIPUR B. PHARMA FINAL YEAR 1


An easy to remember, but limited, nomenclature system makes use of an elemental prefix for the

heteroatom followed by the appropriate carbocyclic name. A short list of some common prefixes

is given in the following table, priority order increasing from right to left. Examples of this

nomenclature are: ethylene oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine

= azabenzene, and morpholine = 1-oxa-4-azacyclohexane.

Element oxygen sulfur selenium nitrogen phosphorous silicon boron

Valence II II II III III IV III

Prefix Oxa Thia Selena Aza Phospha Sila Bora

The Hantzsch-Widman system provides a more systematic method of naming heterocyclic

compounds that is not dependent on prior carbocyclic names. It makes use of the same hetero

atom prefix defined above (dropping the final "a"), followed by a suffix designating ring size and

saturation. As outlined in the following table, each suffix consists of a ring size root (blue) and an

ending intended to designate the degree of unsaturation in the ring. In this respect, it is important

to recognize that the saturated suffix applies only to completely saturated ring systems, and the

unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double

bonds. Systems having a lesser degree of unsaturation require an appropriate prefix, such as

"dihydro"or "tetrahydro".



Ring Size3 4 5 6 7 8 9 10

Suffix

Unsaturate

d

Saturated

irene

irane

ete

etane

ole

olane

ine

i

nane

epine

epane

ocine

o

cane

onine

onane

ecine

ecane

Despite the general systematic structure of the Hantzsch-Widman system, several exceptions and

modifications have been incorporated to accomodate conflicts with prior usage. Some examples

are:

The terminal "e" in the suffix is optional though recommended.

Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the

traditional "iridine", "etidine" & "olidine" suffix.

Unsaturated nitrogen 3-membered heterocycles may use the traditional "irine" suffix.

Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered unsaturated

heterocycles is prevented by their former use for similar Sized nitrogen heterocycles.

Established use of oxine, azine and silane for other compounds or functions prohibits

their use for pyran, pyridine and silacyclohexane respectively.

Note that when a maximally unsaturated ring includes a saturated atom, its location may be

designated by a "#H " prefix to avoid ambiguity, as in pyran and pyrrole above and several

examples below. When numbering a ring with more than one heteroatom, the highest priority

atom is #1 and continues in the direction that gives the next priority atom the lowest number.



All the previous examples have been monocyclic compounds. Polycyclic compounds

incorporating one or more heterocyclic rings are well known. A few of these are shown in the

following diagram. As before, common names are in black and systematic names in blue. The

two quinolines illustrate another nuance of hetrocyclic nomenclature. Thus, the location of a

fused ring may be indicated by a lowercase letter which designates the edge of the heterocyclic

ring involved in the fusion.

Classification (1, 2)

There are a lot of classification for heterocylic compounds but they are very complicated to

understand. The simplest way to classify heterocylic compounds is on the basis of their structural

difference. These are classified according to number of members present in the ring structure.

Simply the heterocylic compounds are classified as follows :-

1. 3-Membered rings



2. 2 4-Membered rings

3. 5-Membered rings

4. 6-Membered rings

5. Heterocyclic amines and cancer

3-Membered rings

Heterocycles with three atoms in the ring are more reactive because of ring strain. Those

containing one heteroatom are, in general, stable. Those with two heteroatoms are more likely to

occur as reactive intermediates. Common 3-membered heterocycles are:

Unsaturated Saturated Heteroatom

Aziridine Nitrogen

Oxirene Ethylene oxide (epoxides,

oxiranes)Oxygen

Thiirane (episulfides) Sulfur

4-Membered rings


Azetidine Nitrogen

Dithiete Oxetane Oxygen

Thietane, dithietane Sulfur



5-Membered rings

With heterocycles containing five atoms, the unsaturated compounds are frequently more stable

because of aromaticity.


Dihydropyrrole

(pyrroline), Pyrrole

tetrahydropyrrole

(pyrrolidine)Nitrogen

FuranDihydrofuran,

tetrahydrofuranOxygen

ThiopheneDihydrothiophene,

tetrahydrothiopheneSulfur

Arsole Arsenic

A large group of 5-membered ring compounds with two heteroatoms are collectively called the

azoles. Dithiolanes have two sulfur atoms.

6-Membered rings

Six membered rings with a single heteroatom:


Pyridine Piperidine Nitrogen

Pyran Tetrahydropyran Oxygen

Thiine (thiapyrane) Thiane Sulfur



With two heteroatoms:


Diazines Piperazine Nitrogen

Oxazine Nitrogen / oxygen

Thiazine Nitrogen / sulfur

Dithiane Sulfur

Dioxane Oxygen

Heterocyclic amines and cancer

Some heterocyclic amines (HCAs) found in cooked meat are known carcinogens. Research has

shown that cooking certain meats at high temperatures creates chemicals that are not present in

uncooked meats. For example, heterocyclic amines are the carcinogenic chemicals formed from

the cooking of muscle meats such as beef, pork, fowl, and fish. HCAs form when amino acids

and creatine (a chemical found in muscles) react at high cooking temperatures. Researchers have

identified 17 different HCAs resulting from the cooking of muscle meats that may pose human

cancer risk. NCI's Division of Cancer Epidemiology and Genetics found a link between

individuals with stomach cancer and the consumption of cooked meat, and other studies for

colorectal, pancreatic, and breast cancer is associated with high intakes of well-done, fried, or

barbecued meats.



PYRIDINE NUCLEUS

Pyridine is a chemical compound with the formula C5H5N. It is a liquid with a distinctively

putrid, fish-like odour. Pyridine is a simple and fundamentally important heterocyclic aromatic

organic compound. It is structurally related to benzene, wherein one CH group in the six-

membered ring is replaced by a nitrogen atom. The pyridine ring occurs in many important

compounds, including the nicotinamides. Pyridine is sometimes used as a ligand in coordination

chemistry. As a ligand, it is usually abbreviated "py".

PYRIDINE, also called azabenzene and azine, is a heterocyclic aromatic tertiary amine

characterized by a six-membered ring structure composed of five carbon atoms and a nitrogen

which replace one carbon-hydrogen unit in the benzene ring (C5H5N). The simplest member of

the pyridine family is pyridine itself. It is colorless, flammable, toxic liquid with a unpleasant

odor, miscible with water and with most organic solvents, boils at 115 C. Its aqueous solution is

slightly alkaline. Its conjugate acid is called pyridinium cation, C5H5NH+, used as a oxidation

agent for organic synthesis..

Pyridine and its derivatives are very important in industrial field as well as in bio chemistry.

Some pyridine system is active in the metabolism in the body. They can be the parent compound

of many drugs, including the barbiturates.

Pyridine and its derivatives are used as solvents and starting material for the synthesis of target

compounds such as insecticides, herbicides, medicines, vitamins, food flavorings, feed additives,

dyes, rubber chemicals, explosives, disinfectants, and adhesives. Pyridine is also used as a

denaturant for antifreeze mixtures, as a dyeing assistant in textiles and in fungicides. Compounds

not made from pyridine but containing its ring structure include niacin and pyridoxal; isoniazid,

nicotine, and several other nitrogenous plant products.



Basicity of Pyridine

The nitrogen atom on pyridine features a basic lone pair of electrons. Because this lone pair is

not delocalized into the aromatic pi-system, pyridine is basic with chemical properties similar

to tertiary amines. The pKa of the conjugate acid is 5.21. Pyridine is protonated by reaction

with acids and forms a positively charged aromatic polyatomic ion called pyridinium cation.

The bond lengths and bond angles in pyridine and the pyridinium ion are almost identical[1]

because protonation does not disrupt the aromatic pi system. In addition, the pyridinium

cation is isoelectronic with benzene.

From heat of combustion measurements, the aromatic stabilization energy of pyridine is 21

kcal/mole. The greater electronegativity of nitrogen (relative to carbon) suggests that such

canonical forms may contribute to a significant degree. Pyridine and its derivatives are weak

bases, reflecting the sp2 hybridization of the nitrogen. From the polar canonical forms shown

here, it should be apparent that electron donating substituents will increase the basicity of a

pyridine, and that substituents on the 2 and 4-positions will influence this basicity more than

an equivalent 3-substituent. The pKa values given in the table illustrate a few of these

substituent effects. Methyl substituted derivatives have the common names picoline (methyl

pyridines), lutidine (dimethyl pyridines) and collidine (trimethyl pyridines). The influence of

2-substituents is complex, consisting of steric hindrance and electrostatic components. 4-

Dimethylaminopyridine is a useful catalyst for acylation reactions carried out in pyridine as a

solvent

The diazines pyrazine, pyrimidine and pyridazine are all weaker bases than pyridine due to

the inductive effect of the second nitrogen. However, the order of base strength is

unexpected. A consideration of the polar contributors helps to explain the difference between

pyrazine and pyrimidine, but the basicity of pyridazine seems anomalous. It has been

suggested that electron pair repulsion involving the vicinal nitrogens destabilizes the neutral

base relative to its conjugate acid.



Pyridine as a solvent

Pyridine is a widely used and versatile solvent: it is polar but aprotic. It is miscible with a

broad range of solvents including hexane and water. Deuterated pyridine, called pyridine-d5,

is a common solvent for1H NMR spectroscopy.

Role in Chemical Synthesis

Pyridine is important in industrial chemistry, both as a fundamental building block and as a

solvent and reagent in organic synthesis.[2] It is used as a solvent in Knoevenagel

condensations.

It is also a starting material in the synthesis of compounds used as an intermediate in making

insecticides, herbicides, pharmaceuticals, food flavorings, dyes, rubber chemicals, adhesives,

paints, explosives and disinfectants. Pyridine is also used as a denaturant for antifreeze

mixtures, for ethyl alcohol, for fungicides, and as a dyeing aid for textiles.

Role in Chemical Analysis

Pyridine, along with barbituric acid, is commonly used in colorimetric determinations of

cyanide in aqueous matrices. Pyridine reacts with cyanogen chloride (formed in an earlier

step by reaction of the cyanide anion with chloramine-T) to form a conjugated species that

couples two molecules of barbituric acid together, forming a red-colored dye. Color intensity

is directly proportional to cyanide concentration.

Pyridine was originally used as the base in the Karl Fischer titration, but has since been

largely replaced by imidazole, which is more basic than pyridine, allowing for a more stable

equivalence point and a faster reaction rate. Imidazole also has the advantage of being

odorless.

Preparation of Pyridine

Many methods exist in industry and in the laboratory (some of them named reactions) for the

synthesis of pyridine and its derivatives: Pyridine was originally isolated industrially from



crude coal tar. It is currently synthesized from acetaldehyde, formaldehyde and ammonia, a

process that involves the intermediacy of acrolein:

CH2O + NH3 + 2 CH3CHO → C5H5N + 3 H2O

By substituting other aldehydes for acetaldehyde, one obtains alkyl and aryl substituted

pyridines. 26,000 tons were produced worldwide in 1989.

The Hantzsch pyridine synthesis is a multicomponent reaction involving formaldehyde, a

keto-ester and a nitrogen donor.

Other examples of the pyridine class can be formed by the reaction of 1,5-diketones with

ammonium acetate in acetic acid followed by oxidation. This reaction is called the

Kröhnke pyridine synthesis.

Pyridinium salts can be obtained in the Zincke reaction.

The Ciamician-Dennstedt Rearrangement (1881) is the ring-expansion of pyrrole with

dichlorocarbene to 3-chloropyridine and HCl

In the Chichibabin pyridine synthesis (Aleksei Chichibabin, 1906) the reactants are three

equivalents of a linear aldehyde and ammonia

In the Gattermann-Skita synthesis (1916) a malonate ester salt reacts with

dichloromethylamine

Synthesis of pyridine derivatives using aza Diels–Alder methodology .

For example: - Hantzsch Dihydropyridine (Pyridine) Synthesis

This reaction allows the preparation of dihydropyridine derivatives by condensation of an

aldehyde with two equivalents of a β-ketoester in the presence of ammonia. Subsequent oxidation

(or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to

yield the corresponding pyridines.



Mechanism

The reaction can be visualized as proceeding through a Knoevenagel Condensation product as a

key intermediate:

A second key intermediate is an ester enamine, which is produced by condensation of the second

equivalent of the β-ketoester with ammonia:

Further condensation between these two fragments gives the dihydropyridine derivative:


http://www.organic-chemistry.org/namedreactions/knoevenagel-condensation.shtm


Synthesis of pyridine derivatives using aza Diels–Alder methodology.

Amidrazone reacted with the unsymmetrical tricarbonyls giving triazines . These

triazines were converted into their corresponding pyridine derivatives in aza Diels–Alder

reactions with 2,5-norbornadiene . Triazines gave the pyridolactones with 2,3-

dihydrofuran



Organic reactions of Pyridine

In organic reactions pyridine behaves both as a tertiary amine, undergoing protonation,

alkylation, acylation, and N-oxidation at nitrogen, and as an aromatic compound, undergoing

Nucleophilic substitutions.

Pyridine is a good nucleophile with a donor number of 33.1. It is easily attacked by

alkylating agents to give N-alkylpyridinium salts.

Nucleophilic aromatic substitution occurs at C2/C4. For example in the Chichibabin

reaction, pyridine reacts with sodium amide to give 2-aminopyridine. In the Emmert

reaction (Bruno Emmert, 1939) pyridine reacts with a ketone in presence of aluminium

or magnesium and mercuric chloride to give the carbinol also at C2.

Electrophilic Substitution of Pyridine

Pyridine is a modest base (pKa=5.2). Since the basic unshared electron pair is not part of the

aromatic sextet, as in pyrrole, pyridinium species produced by N-substitution retain the

aromaticity of pyridine. As shown below, N-alkylation and N-acylation products may be prepared

as stable crystalline solids in the absence of water or other reactive nucleophiles. The N-acyl salts

may serve as acyl transfer agents for the preparation of esters and amides. Because of the stability

of the pyridinium cation, it has been used as a moderating component in complexes with a

number of reactive inorganic compounds. Several examples of these stable and easily handled

reagents are shown at the bottom of the diagram. The poly(hydrogen fluoride) salt is a convenient

source of HF for addition to alkenes and conversion of alcohols to alkyl fluorides, pyridinium

chlorochromate (PCC) and its related dichromate analog are versatile oxidation agents and the

tribromide salt is a convenient source of bromine. Similarly, the reactive compounds sulfur

trioxide and diborane are conveniently and safely handled as pyridine complexes.

Amine oxide derivatives of 3º-amines and pyridine are readily prepared by oxidation with

peracids or peroxides, as shown by the upper right equation. Reduction back to the amine can

usually be achieved by treatment with zinc (or other reactive metals) in dilute acid.



From the previous resonance description of pyridine, we expect this aromatic amine to undergo

electrophilic substitution reactions far less easily than does benzene. Furthermore, as depicted

above the electrophilic reagents and catalysts employed in these reactions coordinate with the

nitrogen electron pair, exacerbating the positive charge at positions 2,4 & 6 of the pyridine ring.

Three examples of the extreme conditions required for electrophilic substitution are shown on the

left. Substituents that block electrophile coordination with nitrogen or reduce the basicity of the

nitrogen facilitate substitution, as demonstrated by the examples in the blue-shaded box at the

lower right, but substitution at C-3 remains dominant. Activating substituents at other locations

also influence the ease and regioselectivity of substitution.

The fused ring heterocycles quinoline and isoquinoline provide additional evidence for the

stability of the pyridine ring. Vigorous permanganate oxidation of quinoline results in

predominant attack on the benzene ring; isoquinoline yields products from cleavage of both rings.

Note that naphthalene is oxidized to phthalic acid in a similar manner. By contrast, the

heterocyclic ring in both compounds undergoes preferential catalytic hydrogenation to yield

tetrahydroproducts. Electrophilic nitration, halogenation and sulfonation generally take place at

C-5 and C-8 of the benzene ring, in agreement with the preceeding description of similar pyridine

reactions and the kinetically favored substitution of naphthalene at C-1 (α) rather than C-2 (β).



Other Reactions of Pyridine

Thanks to the nitrogen in the ring, pyridine compounds undergo nucleophilic substitution

reactions more easily than equivalent benzene derivatives. In the following diagram, reaction 1

illustrates displacement of a 2-chloro substituent by ethoxide anion. The addition-elimination

mechanism shown for this reaction is helped by nitrogen's ability to support a negative charge. A

similar intermediate may be written for substitution of a 4-halopyridine, but substitution at the 3-

position is prohibited by the the failure to create an intermediate of this kind. The two

Chichibabin aminations in reactions 2 and 3 are remarkable in that the leaving anion is hydride

(or an equivalent). Hydrogen is often evolved in the course of these reactions. In accord with this

mechanism, quinoline is aminated at both C-2 and C-4.

Addition of strong nucleophiles to N-oxide derivatives of pyridine proceed more rapidly than to

pyridine itself, as demonstrated by reactions 4 and 5. The dihydro-pyridine intermediate easily

loses water or its equivalent by elimination of the –OM substituent on nitrogen.



Derivatives of Pyridine

Pyridine-borane, C5H5NBH3 (m.p. 10–11 °C) is a mild reducing agent with improved

stability relative to NaBH4 in protic solvents and improved solubility in aprotic organic

solvents.

Pyridine-sulfur trioxide, C5H5NSO3 (mp 175 °C) is a sulfonation agent used to convert

alcohols to sulfonates, which in turn undergo C-O bond scission upon reduction with

hydride agents.

Related compounds

Structurally or chemically related compounds are

DMAP is short for 4-dimethylaminopyridine

Bipyridine and viologen are simple polypyridine compounds consisting of two pyridine

molecules joined by a single bond

Terpyridine, a molecule of three pyridine rings connected together by two single bonds.

Quinoline and Isoquinoline have pyridine and a benzene ring fused together.

Aniline is a benzene derivative with an attached NH2 group and NOT a pyridine

Diazines are compounds with one more carbon replaced by nitrogen such as Pyrazine and

Pyramidine



Triazines are compounds with two more carbons replaced by nitrogen and a tetrazine has

four nitrogen atoms

2,6-Lutidine is a trivial name for 2,6-dimethylpyridine.

Collidine is the trivial name for 2,4,6-trimethylpyridine.

Pyridinium p-toluenesulfonate (PPTS) is a salt formed by proton exchange between

pyridine and p-toluenesulfonic acid

2-Chloropyridine is a toxic environmentally significant component of the breakdown of

the pesticide imidacloprid.

Microbial Metabolism of the Pyridine Ring

THE METABOLISM OF PYRIDINE-3,4-DIOL (3,4-DIHYDROXYPYRIDINE) BY

AGROBACTERIUM SP.

Pyridine-3,4-diol (3,4-dihydroxypyridine, 3-hydroxypyrid-4-one), an intermediate in 4-

hydroxypyridine metabolism by an Agrobacterium sp (N.C.I.B. 10413), was converted

by extracts into 1 mol of pyruvate, 2mol of formate and 1 mol ofNH3 at pH7.0.

Formate, but not the alternative likely product formamide, was further oxidized fivefold

faster by 4-hydroxypyridine-grown washed cells than by similar organisms grown on

succinate.

The oxidation of pyridine-3,4-diol by crude extracts at pH8.5 required 1 mol of 02/molof

substrate, produced 1 mol of acid and led to the formation of formate and a new

compoundwith an extinction maximum of 285nm (Compound I). This step was believed

tobe mediated by a new labile dioxygenase (tQ = 4h at pH7.0, 4°C) cleaving the pyridine

ringbetween C-2 and C-3.

Many of the properties of this pyridine-3,4-diol dioxygenaseparalleled those of the

extradiol ('meta') oxygenases of aromatic-ring cleavage. Theextreme lability of the

enzyme has so far precluded extensive purification.



Compound Ishowed changes in the u.v.-absorption spectrum with pH but after

acidification it wasconverted into a new product, 3-formylpyruvate, with an extinction

maximum now at279nm.

Both Compound I and 3-formylpyruvate were metabolized by extracts but at very

different rates. The slower rate of metabolism of Compound I was nevertheless consistent

with that of pyridine-3,4-diol metabolism.

On acidification Compound I released about 0.65mol of NH3 and has been identified as

3-formiminopyruvate.

3-Formylpyruvate was hydrolysed to formate and pyruvate (K,, 2/CM) by an

acylpyruvate hydrolase active against several other dioxo homologues. The activity of

this enzyme was much lower in extracts of succinate-grown cells.

Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine



Introduction:

Malaria affects 40% of global population and accounts annually for 300 to 500 million clinical

cases with 1.5 to 2.7 million deaths. The burden of malaria is increasing because of drug

resistance, and there is an urgent need for new antimalarial drugs. Intra-erythrocytic stages of

malaria parasites consume and degrade huge quantities of hemoglobin in the food vacuole and

release large quantities of redox active free heme as a by-product . Free heme (ferriprotoporphyrin

IX) is very toxic , and parasites detoxify free heme by forming hemozoin, mainly through the

biocrystallization or biomineralization process . Molecules that inhibit parasite growth through

binding to heme are potential antimalarials, and the inhibition of hemozoin formation is

considered a valid target for developing new antimalarials. Again, the inhibition of hemozoin

formation may develop oxidative stress due to the accumulation of free heme, which can generate

highly reactive hydroxyl radical (·OH), and the malaria parasite is susceptible to oxidative stress.

Therefore, the enhancement of oxidative stress to the parasite by any means is a promising

strategy in developing new antimalarial agents.

Triarylmethanes represent an important class of medicinally important molecules and are known

to possess a wide variety of biological activities such as antitubercular, anti-implantation , and

antiproliferative activities and activity against breast cancer . The potent antimycotic drug

clotrimazole, a member of the triarylmethanes, inhibits the in vitro parasite growth of different

strains of chloroquine-sensitive and -resistant Plasmodium falciparum . Very recently,

antimalarial agents based on the clotrimazole scaffold have been synthesized . Again,

trisubstituted methanes (TRSMs) containing sulfide, sulfoxide, or sulfone spacers have also been

reported to show various biological activities. A small set of 9-(lupinylthio)xanthenes, 9-

(lupinylthio)thioxanthenes, and a-(lupinylthio)diphenylmethanes was found to exhibit diverse

biological activities . Arylsulfanyl and arylsulfonyl moities are integral parts of many antimalarial

agents. For example, the antimalarial activity of several arylacridinyl sulfones has been reported

recently . Furoxan derivatives bearing a sulfone moiety were reported to have antimalarial activity

. A series of imidazole-dioxolane compounds bind to the heme and showed promising anti-

Plasmodium activity . These results prompted us to synthesize and evaluate a new series of

TRSMs for antimalarial efficacy. Here we report the antimalarial activity of a series of

[(aryl)arylsufanylmethyl]pyridines (AASMPs) that represents a new class of TRSMs. Our work

focused on the evaluation of the antimalarial activity of these compounds, including the

mechanistic details on the effect of heme interaction, hemozoin formation, and in vitro and in

vivo antimalarial effect.



Chemistry:

Our method for the synthesis of AASMPs involved S alkylation of different aryl or heteroaryl

thiols using carbinols 3a and 3b as the alkylating agents . The formation of a sulfur link between a

diarylmethane and an aryl or a heteroaryl ring can be achieved either by the nucleophilic attack of

an aryl or heteroarylthiolate anion on diarylmethyl halides and diarylmethyl-p-tolylsulfonates or

by protic or Lewis acid-catalyzed condensation of diarylcarbinols with different aryl or

heteroarylthiols . Carbinols 3a and 3b were obtained by the Grignard reaction of 4-

methoxyphenylmagnesium bromide 1 with pyridine-3-carbaldehyde and pyridine-2-aldehyde,

respectively. The S alkylation reactions on carbinols 3a and 3b were achieved in the presence of

anhydrous AlCl3 (1.1 eq) in dry benzene at room temperature. However, in the case of S

alkylation of 2-mercaptobenzothiazole on carbinol 3a the reaction was performed at reflux

condition since 2-mercaptobenzothiazole is insoluble in benzene at room temperature. Although

in every case the reaction condition was like that of a typical Friedel-Crafts alkylation reaction

due to the higher nucleophilicity of sulfur than that of aromatic ring carbon atoms, nucleophilic

attack occurred through sulfur.

Discussion:

AASMP has antiplasmodial activity. The mechanistic studies reveal that it effectively inhibits

hemozoin formation and induces oxidative stress in the malaria parasite to inhibit P. falciparum

growth. The data indicate that this novel class of antimalarial shows selective activity against the

malaria parasite with a selectivity index of greater than 100 and offers antimalarial activity in vivo

in the rodent model

Compounds that inhibit hemozoin formation usually interact with heme. The addition of AASMP

clearly perturbed the heme spectrum, a finding indicative of an interaction between the AASMP

and the heme units. The spectral changes of heme-AASMP mixtures were similar to those

observed for molecular complex formation between metalloporphyrines and other aromatic

molecules involving a cofacial - interaction

The possible mechanism by which AASMP develops oxidative stress and parasite death is

mediated through its inhibitory effect on hemozoin formation. The inhibition of hemozoin

formation causes death of the parasite due to the accumulation of toxic free heme . Free heme can

damage cellular metabolism of the malaria parasite by inhibiting enzymes, promoting the

peroxidation of membranes and the production of reactive oxygen species in the acidic

environment of the food vacuole . It also well known that the malaria parasite is very much



susceptible to oxidative stress . Inhibition of heme detoxification function is known to kill the

parasite through membrane lysis and the interference of other vital function.



SOME COMPOUNDS CONTAINING PYRIDINE NUCLEUSSOME COMPOUNDS CONTAINING PYRIDINE NUCLEUS

Amlodipine besylate

Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-

aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-

pyridinedicarboxylate, monobenzenesulphonate . Its empirical formula is

C20H25CIN2O5•C6H6O3S, and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1 .

Therapeutic use:

Hypertension

Coronary Artery Disease (CAD)

Chronic Stable Angina

Vasospastic Angina (Prinzmetal's or Variant Angina)

Angiographically Documented CAD



Note : NORVASC has been safely administered with thiazides, ACE inhibitors, beta-blockers,

long-acting nitrates, and/or sublingual nitroglycerin.

Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel

blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and

cardiac muscle. The contractile processes of cardiac muscle and vascular smooth muscle are

dependent upon the movement of extracellular calcium ions into these cells through specific ion

channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a

greater effect on vascular smooth muscle cells than on cardiac muscle cells.

Side Effects

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation),

bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural

dizziness, postural hypotension, vasculitis.

Other side effects are:

Edema

Dizziness

Flushing

Palpitation

Headache

Fatigue

Nausea

Abdominal pain


http://www.rxlist.com/script/main/art.asp?articlekey=7075




















Clopidogrel bisulfate

Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-

acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and

its molecular weight is 419.9.

The structural formula is as follows:

Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral

pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in

methylene chloride, and is practically insoluble in ethyl ether.

Therapeutic use :

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

Acute Coronary Syndrome

Mechanism of action:

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function

have been shown to decrease morbid events in people with established cardiovascular

atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial

infarction, unstable angina or the need for vascular bypass or angioplasty.












Side Effect

Chest Pain

Fatigue

Edema

Hypertension

Dizziness

Dyspepsia

Nausea

Epistaxis

Rhinitis

Dyspnea



Isoniazid

Isoniazid is an antibacterial available as 100 mg or 300 mg tablets for oral administration.

Isoniazid is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. Isoniazid

is odorless, and occurs as a colorless or white crystalline powder or as white crystals. It is freely

soluble in water, sparingly soluble in alcohol, and slightly soluble in chloroform and in ether.

Isoniazid is slowly affected by exposure to air and light.

Therapeutic use

Mainly ISONIAZID is used for the treatment of Tuberculosis. Isoniazid is used in conjunction

with other anti-tuberculosis agents. Drug susceptibility testing should be performed on the

organisms initially isolated fro all patients with newl diagnosed tuberculosis. If the bacilli

becomes resistant, therapy must be changed to agents to which the bacilli are susceptible.

Mechanism of Action

Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell

wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and

extracellular Mycobacterium tuberculosis organisms lsoniazid resistant Mycobacterium

tuberculosis bacilli develop rapidly when lsoniazid monotherapy is administered.

















Side Effects

The most frequent reactions are those affecting the nervous system and the liver.

Nervous System Reactions : The most common toxic effect are neuritis, convulsions,

toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic

psychosis.

Hepatic Reactions : Elevated serum transaminase (SGOT SGPT), bilirubinemia,

bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis.

Gastrointestinal Reactions : Nausea, vomiting, and epigastric distress.
















Niacin

Niacin (nicotinic acid, or 3-pyridinecarboxylic acid) is a white, crystalline powder, very soluble

in water, with the following structural formula:

Therapeutic use

Niacine is used in the treatment of hyperlipidemia because it reduces very low density

lipoprotein(VLDL) , a precursor of low density lipoprotein or bad cholesterol.

Mechanism of Action

The mechanism by which niacin alters lipid profiles has not been well defined. It may involve

several actions including partial inhibition of release of free fatty acid from adipose tissue, and

increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride

from plasma. Niacin decreases the rate of hepatic synthesis of VLDL and LDL, and does not

appear to affect fecal excretion of fats,sterol or bile acids.

Side effects:

Dizziness

Tachycardia

Palpitations

Shortness of breath

Sweating

Chills

Edema

Cardiac arrhythmias

Tachycardia









Ulceration

Jaundice

Eructation

Dyspnea







Nicotine:Structural Formula:

Chemical Name: S-3-(1-methyl-2-pyrrolidinyl) pyridine

Molecular Formula: C10H14N2

Molecular Weight: 162.23

Ionization Constants: pKa1 = 7.84, pKa2 = 3.04 at 15° C

Octanol-Water Partition Coefficient: 15:1 at pH 7

Nicotine is a tertiary amine composed of a pyridine and a pyrrolidine ring. It is a colorless to pale

yellow, freely water-soluble, strongly alkaline, oily, volatile, hygroscopic liquid obtained from

the tobacco plant. Nicotine has a characteristic pungent odor and turns brown on exposure to air

or light. Of its two stereoisomers, S(-) nicotine is the more active.

Pharmacologic Action

Nicotine, the chief alkaloid in tobacco products, binds stereo-selectively to nicotinic-cholinergic

receptors at the autonomic ganglia, in the adrenal medulla, at neuromuscular junctions, and in the

brain. Two types of central nervous system effects are believed to be the basis of nicotines

positively reinforcing properties. A stimulating effect is exerted mainly in the cortex via the locus

ceruleus and a reward effect is exerted in the limbic system. At low doses the stimulant effects

predominate while at high doses the reward effects predominate. Intermittent intravenous

administration of nicotine activates neurohormonal pathways, releasing acetylcholine,

norepinephrine, dopamine, serotonin, vasopressin, beta-endorphin, growth hormone, and ACTH.




















Side Effects

The main side effect is drug dependence. And the other adverse events are:

Local Irritation

Dizziness

Anxiety

Sleep disorder

Depression

Fatigue

Nausea

Nifedipine-:

Nifedipine is an antianginal drug belonging to a class of pharmacological agents, the calcium

channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2, 6-dimethyl-4-(2-

nitrophenyl)-, dimethyl ester, C17H18N2O6, and has the structural formula:

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol.

It has a molecular weight of 346.3.

Therapeutic use:

Vasospastic Angina









Chronic Stable Angina

Mechanism of action:

The precise means by which this inhibition relieves angina has not been fully determined, but

includes at least the following two mechanisms:

Relaxation and Prevention of Coronary Artery Spasm

Reduction of Oxygen Utilization

Side iffects:

Dizziness, lightheadedness, giddiness

Flushing, heat sensation

Headache

Weakness

Nausea, heartburn

Muscle cramps, tremor

Nervousness, mood changes

Palpitation

Dyspnea, cough, wheezing

Nasal congestion, sore throat

Pirbuterol

Pirbuterol acetate is a white, crystalline racemic mixture of two optically active isomers. It is a

powder, freely soluble in water, with a molecular weight of 300.3.



Pharmacological actions :

Pirbuterol is indicated for the prevention and reversal of bronchospasm in patients 12 years of age

and older with reversible bronchospasm including asthma . It may be used with or without

concurrent theophylline and/or corticosteroid therapy.

Mechanism of action :

Pirbuterol is a beta adrenergic agonist which stimulates intracellular adenyl cyclase, which

catalyzes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (c-AMP).

Increased c-AMP levels are associated with relaxation of bronchial smooth muscle.

Side effects:

Seizures

angina

hypertension

arrhythmias

nervousness

headache

dry mouth

palpitation

nausea

dizziness

fatigue
















Piroxicam

Piroxicam is a member of the oxicam group of nonsteroidal anti-inflammatory drugs

(NSAIDs). The chemical name for piroxicam is 4-hydroxyl-2-methyl-N-2-pyridinyl-2H-

1,2,-benzothiazine-3-carboxamide 1,1-dioxide. Piroxicam occurs as a white crystalline

solid, sparingly soluble in water, dilute acid and most organic solvents. It is slightly

soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton

(pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of

piroxicam is 331.35. Its molecular formula is C15H13N3O4S and it has the following

structural formula:

Therapeutic use :

For relief of the signs and symptoms of osteoarthritis.

For relief of the signs and symptoms of rheumatoid arthritis

Mechanism of action :

The mechanism of action of pirbuterol like that of other NSAIDs, is not completely

understood but may be related to prostaglandin synthetase inhibition .

Side effects :.

Anorexia

Abdominal pain

Constipation








Diarrhea

Vomiting.

Dizziness

Headache

Fever.

Congestive heart failure

Hypertension

Tachycardia.

Dry mouth

Anxiety

Drowsiness

Blurred vision.











Pralidoxime Chloride

Chemical name: 2-formyl-1-methylpyridinium chloride oxime. Available in the United States as

Protopam Chloride, pralidoxime chloride is frequently referred to as 2-PAM Chloride.

Pralidoxime chloride occurs as an odorless, white, nonhygroscopic, crystalline powder which is

soluble in water to the extent of 1 g in less than 1 mL. Stable in air, it melts between 215° and

225°C, with decomposition. The chloride is preferred because of physiologic compatibility,

excellent water solubility at all temperatures

Therapeutic use :

Mainly pralidoxime is used to reactivate cholinesterase (i.e. it is used in organophosphate

poisoning.

ORGANOPHOSPHATE POISONING

ANTICHOLINESTERASE OVERDOSAGE

Side effects :

Forty to 60 minutes after intramuscular injection, mild to moderate pain may be experienced at

the site of injection.

When given parenterally to normal volunteers who have not been exposed to

anticholinesterase poisons Pralidoxime may cause

Blurred vision







Diplopia

Dizziness

Headache

Drowsiness

Nausea

Tachycardia

Increased systolic and diastolic pressure

Hyperventilation

Muscle weakness



Pyridostigmine Bromide

Pyridostigmine is an orally active cholinesterase inhibitor. Chemically, pyridostigmine bromide is

3-hydroxy-1-methylpyridinium bromide dimethylcarbamate. Its structural formula is:

Therapeutic use:

Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis and to

combat the effects of curariform drug toxicity.

Pyridostigmine bromide has been FDA approved for military use during combat

situations as an agent to be given prior to exposure to the nerve agent Soman in order to

increase survival (it has been used in particular during the first Gulf War).

Pyridostigmine is now also used to treat orthostatic hypotension.

Pyridostigmine bromide is available under the trade names Mestinon (Valeant

Pharmaceuticals) and Regonol.

Mechanism of action

In order to understand the mode of action, a quick outline of a synapse is given below. For more

information, look up synapse. Action potentials are conducted along motor nerves to their

terminals where they initiate a Ca2+ influx and the release of acetylcholine (ACh). The ACh

diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing

an influx of Na+ and K+ ions, resulting in depolarisation. If large enough, this depolarisation

results in an action potential. In order to prevent constant stimulation once the ACh is released, an

enzyme called acetylcholinesterase is present in the endplate membrane close to the receptors on

the post synaptic membrane, and quickly hydrolizes ACh.

Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the

hydrolysis of acetylcholine.


http://en.wikipedia.org/wiki/Acetylcholine

http://en.wikipedia.org/wiki/Synaptic_cleft

http://en.wikipedia.org/wiki/Acetylcholinesterase

http://en.wikipedia.org/wiki/Potassium

http://en.wikipedia.org/wiki/Sodium

http://en.wikipedia.org/wiki/Acetylcholine

http://en.wikipedia.org/wiki/Action_potential

http://en.wikipedia.org/wiki/Synapse

http://en.wikipedia.org/wiki/Valeant_Pharmaceuticals_International

http://en.wikipedia.org/wiki/Valeant_Pharmaceuticals_International

http://en.wikipedia.org/wiki/Orthostatic_hypotension

http://en.wikipedia.org/wiki/Gulf_War

http://en.wikipedia.org/wiki/Soman

http://en.wikipedia.org/wiki/Curare

http://en.wikipedia.org/wiki/Myasthenia_gravis


Side effects:

The side effects of pyridostigmine are most commonly related to overdosage and generally are of

two varieties, muscarinic and nicotinic. Side effects are:

nausea,

vomiting,

diarrhea,

abdominal cramps,

increased peristalsis, salivation, and bronchial secretions,

miosis and diaphoresis.

Nicotinic side effects are comprised chiefly of muscle cramps, fasciculation and

weakness.








Quinidine

Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with Class la activity; it is

the d-isomer of quinine, and its molecular weight is 324.43. Quinidine sulfate is the sulfate salt of

quinidine; its chemical name is cinchonan-9-ol, 6'-methoxy-, (9S)-, sulfate(2:1) dihydrate.

Therapeutic uses:

By slowing conduction and prolonging the effective refractory period, quinidine can be used in :

Atrial fibrillation or flutter.

Paroxysmal supraventricular tachycardia.

Maintenance of sinus rhythm following electroconversion.

Mechanisms of Action

In patients with malaria, quinidine acts primarily as an intra-erythrocytic schizonticide, with little

effect upon sporozites or upon pre-erythrocytic parasites.

In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing

sodium current, thereby slowing phase-0 depolarization and reducing the amplitude of the action

potential without affecting the resting potential. . The result is slowed conduction and reduced

automaticity in all parts of the heart, with increase of the effective refractory period.










Quinidine is gametocidal to Plasmodium vivax and P. malariae, but not to P. falciparum. So it is

also used in malaria.

Side effects:

Diarrhea

Nausea

Vomiting

Heart burn

Deafness

Blurred vision

Diplopia

Vertigo

Delirium

Mydriasis

Night blindness




Torsemide

Torsemide is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-[(4-

m-toluidino-3-pyridyl) sulfonylurea and its structural formula is:

Its empirical formula is C16H20N4O3S, its pKa is 7.1, and its molecular weight is

348.43.Torsemide is a white to off-white crystalline powder.

Therapeutic use :

Congestive Heart Failure

Chronic Renal Failure

Hepatic Cirrhosis

Hypertension

Side effects :

Dizziness

Headache

Nausea

Weakness

Vomiting







Hyperglycemia

Excessive urination

Hyperuricemia

Hypokalemia

Excessive thirst

Hypovolemia

Impotence

Oesophageal hemorrhage

Dyspepsia.











AZATADINEC20H22N2 (290.41)

CHEMICAL NAME(S): 6,11-Dihydro-11-(-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-

beta]pyridine;

BROMPHENIRAMINE

C16H19BrN2 (319.24)

CHEMICAL NAME(S): R-(4-bromophenyl)N, N-dimethyl-2-Pyridinepropanamine



CARBINOXAMINE

C16H19ClN2O (290.79)

DEXCHLORPHENIRAMINE C16H19ClN2 (274.7)



DOXYLAMINEC17H22N2O (270.37)

2]-alpha-[2-(Dimethylamino)ethoxy]-alpha-methylbenzyl-[Pyridine

LORATADINEC22H23ClN2O2 (382.89)

CHEMICAL NAME(S):

Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta[1,2-b] pyridin-11- ylidene)-1-piperidine

carboxylate; Claratyne

PYRILAMINEC17H23N3O (285.39)

CHEMICAL NAME(S):

N-[(4-methoxyphenyl)methyl]-N',N'-dimethyl-N-2-pyridinyl-1,2-Ethanediamine



TRIPELENNAMINE

C16H21N3 (255.36)

CHEMICAL NAME(S):

N,N-dimethyl-N'-(phenylmethyl)-N'-2-pyridinyl-1,2-Ethanediamine; 2-[benzyl[2-

(dimethylamino)ethyl]amino]-Pyridine

TRIPROLIDINE C19H22N2 (278.40)



CONCLUSION

Pyridine is a six-membered heterocyclic aromatic organic compound. Pyridine is an aromatic

tertiary amine.

Pyridine and its derivatives are very important in industrial field as well as in bio chemistry.

Pyridine and its derivatives are used as solvents and starting material for the synthesis of target,

dyes, rubber chemicals, explosives, disinfectants, and adhesives.compounds such as insecticides,

herbicides, medicines, vitamins, food flavorings, feed additive.

Many drugs containing pyridine ring are used in various pharmaceutical preparation but these can

not be categorized into a single group (i.e. they are used for the treatment of various

abnormalities). For example:

Amlodipine is used as an anti hypertensive agent; Clopidogrel is an inhibitor of platelet

aggregation ; Isoniazid is an antibacterial agent; niacin is used in the treatment of hyperlipidemia;

Nifedipine is an antianginal drug; Pirbuterol is a beta adrenergic agonist; pralidoxime is used to

reactivate cholinesterase (i.e. it is used in organophosphate poisoning); Pyridostigmine is used as

a cholinergic agent; Quinidine is an antimalarial agent; Torsemide is a diuretic etc.








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