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Hetero Cyclic Compounds

Hetero Cyclic Compounds

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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

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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 Valence Prefix

oxygen II Oxa

sulfur II Thia

selenium II Selena

nitrogen III Aza

phosphorous III Phospha

silicon IV Sila

boron III 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 Size

3

4

5

6

7

8

9

10

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Suffix Unsaturate irene Saturated ete ole ine inan e epine epane ocine ocan e onine ecine

d irane etane olane

onane 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

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Heterocyclic Compound
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 Membered rings-3 .1 Membered rings-4 2.2 Membered rings-5.3 Membered rings-6.4 Heterocyclic amines and cancer.5

Membered rings-3•
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

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Unsaturated Saturated Aziridine Oxirene Ethylene oxide (epoxides, (oxiranes (Thiirane (episulfides Heteroatom Nitrogen Oxygen Sulfur

Membered rings-4•
Unsaturated Saturated Azetidine Dithiete Oxetane Thietane, dithietane Heteroatom Nitrogen Oxygen Sulfur

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Membered rings-5•
With heterocycles containing five atoms, the unsaturated compounds are frequently more stable .because of aromaticity

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:With two heteroatoms Unsaturated Diazines Saturated Piperazine Oxazine Thiazine Dithiane Dioxane Heteroatom Nitrogen Nitrogen / oxygen Nitrogen / sulfur Sulfur 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

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Heterocyclic Compound

PYRIDINE NUCLEUS

Pyridine

is

a

chemical

compound

with

the

formula

C5HYPERLINK

"http://en.wikipedia.org/wiki/Hydrogen"H5HYPERLINK "http://en.wikipedia.org/wiki/Nitrogen"N. 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

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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. 4Dimethylaminopyridine 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•

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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

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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

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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

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Heterocyclic Compound

.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 2,3dihydrofuran

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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

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Heterocyclic Compound

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

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Heterocyclic Compound

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 3position 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

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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•

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Heterocyclic Compound
four nitrogen atoms .Lutidine is a trivial name for 2,6-dimethylpyridine-2,6• .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 Chloropyridine is a toxic environmentally significant component of the breakdown of -2• .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

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

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Heterocyclic Compound
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 antiPlasmodium 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

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Heterocyclic Compound
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 4methoxyphenylmagnesium 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

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Heterocyclic Compound

SOME COMPOUNDS CONTAINING PYRIDINE NUCLEUS Amlodipine besylate
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylate, 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

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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•

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Heterocyclic Compound

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

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

Heterocyclic Compound

Side Effect
Chest Pain• Fatigue• Edema• Hypertension• Dizziness• Dyspepsia• Nausea• Epistaxis• Rhinitis• Dyspnea•

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Heterocyclic Compound

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

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Heterocyclic Compound
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•

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Heterocyclic Compound

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•
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Heterocyclic Compound
Dyspnea•

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Heterocyclic Compound

: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

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Heterocyclic Compound
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

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Heterocyclic Compound
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

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Heterocyclic Compound
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•

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Heterocyclic Compound

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-2H1,2,-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•

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Heterocyclic Compound
.Vomiting• Dizziness• Headache• .Fever• Congestive heart failure• Hypertension• .Tachycardia• Dry mouth• Anxiety• Drowsiness• .Blurred vision•

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Heterocyclic Compound

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•

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

Heterocyclic Compound
Drowsiness• Nausea• Tachycardia• Increased systolic and diastolic pressure• Hyperventilation• Muscle weakness•

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Heterocyclic Compound

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

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Heterocyclic Compound

: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

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Heterocyclic Compound

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

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Heterocyclic Compound

:Side effects
Diarrhea• Nausea• Vomiting• Heart burn• Deafness• Blurred vision• Diplopia• Vertigo• Delirium• Mydriasis• Night blindness•

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Heterocyclic Compound

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•

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

Heterocyclic Compound Excessive thirst• Hypovolemia• Impotence• Oesophageal hemorrhage• .Dyspepsia•

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

Heterocyclic Compound

AZATADINE
(C20H22N2 (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

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Heterocyclic Compound

CARBINOXAMINE
(C16H19ClN2O (290.79

DEXCHLORPHENIRAMINE
(C16H19ClN2 (274.7

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Heterocyclic Compound

DOXYLAMINE
(C17H22N2O (270.37

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

LORATADINE
(C22H23ClN2O2 (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

PYRILAMINE
(C17H23N3O (285.39

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

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Heterocyclic Compound

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

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Heterocyclic Compound

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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Heterocyclic Compound

BIBLIOGRAPHY
Eicher, T.; Hauptmann, S, (2003), “ The Chemistry of Heterocycles: Structure, .1 Reactions, Syntheses, and Applications” : 2nd ed.; Wiley-VCH. ISBN 3527307206 Heterocyclic Amines in Cooked Meats"; National Cancer Institute (15 Sep 2004). ".2 .Retrieved on 2007: 96-98 Gattermann-Skita @ Institute of Chemistry, Skopje, Macedonia.3 Sherman, A. R. “Pyridine in e-EROS (Encyclopedia of Reagents for Organic .4 .Synthesis)” 2004, J. Wiley & Sons, New York :345-47 Mulder G etal,(1986) “Sex differences in drug conjugation and their consequences.5 .for drug toxicity, Sulfation, glucuronidation and glutathione conjugation”: 427-31 Prakash C, Kamel A, and Cui D, (1997) : “Characterization of the novel.6 benzisothiazole ring cleaved products of the antipsychotic drug”; Drug Metab Dispos 25: 897-901 Choubey V. and U. Bandyopadhyay etal (2007) “Inhibition of Plasmodium.7 falciparum choline kinase by hexadecyltrimethylammonium bromide: a possible .antimalarial mechanism. Antimicrob. Agents Chemother”; 51:696-706 Biswas, K etal (2003)., “A novel antioxidant and antiapoptotic role of omeprazole to.8 block gastric ulcer through scavenging of hydroxyl radical. J. Biol. Chem.” .278:10993-11001 Graham L. Patrick (2001) “An introduction to medicinal chemistry” oxford .9 .university press; 1st edition; 772-74,1037-45 Foyes principal of medicinal chemistry” Lippincot Williams & wilkins,“.10 .international; 5th edition: 54,115,331 Lippincott Williams & wilkins, “Remington: The science and practice of pharmacy” .11 International student edition ; 20th edition

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David A. Williams’s et.al (1974) “principal of medicinal chemistry”1st edition.12 Mittal MK etal(2007): "Toxicity from the use of niacin to beat urine drug screening". .13 .Ann Emerg Med 50 (5): 587–90 Tripathi K.D. (2004); “Essential of medical pharmacology”Jaypee brothers medical.14 .publishers; 5th edition; 321-37 Satoskar R.S. et.al (2003) “Pharmacotherapeutics” Popular prakashan pvt. Ltd.; 18th.15 edition Aushutoshkar (1992); “Medicinal Chemistry”; new age international publishers; 2nd.16 edition; 523-525 V.N. Sharma (1999); “Essential of Pharmacology”; CBS publishers; 1st edition.17 Pandey S.N. (2005); “Medicinal chemistry” CBS Publisher and distributor; 11th.18 .edition; 2:186-92 Kadam S.S et.al(2006) “Principle of medicinal chemistry” Nirali prakashan,16th.19 .edition; 2 : 265, 268 LANDAUER,( 1977); “Cholinomimetic teratogens. V. The effect of oximes and.20 ”related cholinesterase reactivators, Teratology MOLLER, K.O., JENSEN-HOLM, J., and LAUSEN, H.H.: Ugeskr. Laeg. 123 :501,.21 1961 Grob D.,(Oct 1961) “Myasthenia gravis: A review of pathogenesis and treatment”; .22 .Arch Intern Med.; 108:615-638 Osserman KE and Genkins G.( June 1961) “Studies in myastheniagravis” NY State J .23 .Med.;61:2076-2085 Singh Harikishan “medicinal & phapmaceutical chemistry”vallabh prakashan”1st.24 .edition

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