LectureLecture № №66Heterocyclic antibioticsHeterocyclic antibiotics: : aminoglycosidesaminoglycosides, ,

macrolidesmacrolides. . Polypeptide antibioticsPolypeptide antibiotics, , polyenespolyenes andand antitumor antibiotics. antitumor antibiotics.

Fluoroquinolone as antibiotic drugs.as antibiotic drugs.

prepared ass. Kozachok S.S.prepared ass. Kozachok S.S.

AminoglycosidesAminoglycosides divided on the divided on the following groupsfollowing groups::

StrepyomycinStrepyomycin ( (separately separately ,, NH NH22- - group is group is

substitutesubstitutedd););

Aminoglycosides Aminoglycosides ((kanamycinkanamycin, , neomycinneomycin, , gentamycingentamycin, , monomycinmonomycin, , amikacinamikacin););

MacrolidesMacrolides ( (erythromycinerythromycin, , oleandomycinoleandomycin, , roxitromycinroxitromycin, , claritromicinclaritromicin, , dirythromycindirythromycin, , spiramycinspiramycin, , azitromycinazitromycin););

AnsamycinAnsamycin ((rrififampicinampicin))

Strepyomycin sulfate (Streptomycini sulfas) Streptomycin sulfate* (UP)

Bis-[N,N’-bis(aminoiminomethyl)-4-O-[5-deoxy-2-O-[2-deoxy-2-methylamino)-α-L-glucopyranosyl]-3-С-formyl-

α-L -lyxofuranosyl]-D-streptamine] trisulfate

• Streptomycin, discovered in 1944 by the American scientist Waxman.

• Obtaining. Microbiological synthesis from Streptomyces griseus actinomycetes.

• Streptomycin glycoside consists of the aglycone - streptydin (1,3-diguanidino-2,4,5,6-tetraoxycyclohexan) and sugar part-disaccharide streptobiozamine (N-methyl-L-glucosamine and L-streptos).

CHARACTERISTICS• White powder. Hygroscopic . Very soluble in

water, practically insoluble in ethanol and ether.• Streptomycin has a basic property according to

the appearance of the nitrogen containing group (two guanidins and one N-methylamino) that’s why easy creates salts.

• In a weak acidic medium streptomycin is stable, but in strong acidic and especially in basic medium it easy hydrolyzes on a streptydin and streptobiozamine, which decomposes on N-methyl-L-glucosamine and L-streptos.

Identification • TLC.• Maltol test is caused by the ability of the streptos in a

basic medium to convert on a maltol according to the dehydratation and isomerization. At the iron (III) ions interaction in an acidic medium maltol forms the violet products:

Maltol (α-methyl-β-oxy-γ-piron)

OHCH3

OH OH

CHO

O

O

O

OH

CH3

FeNH4(SO4)2

H2SO4

O

O

O

CH3

NaOH, t0C

Fe3+/3

• Sakaguchi reaction on the remnants of guanidines. Formation of a violet-red colour, which appearances in a basic medium under the action of -naphthol and concentrated sodium hypochlorite.

• Molish reaction on carbohydrates (streptos). After acidic hydrolysis the substance does not give reaction with -naphthol and concentrated sodium hypochlorite in a basic solution. Yellow colour.

• It gives the reaction of sulfate.

O

N

Br

OH

C NH

NH

R

• Un pharmacopoeia reaction :

a) Escaping of ammonia by heating of the substance with sodium hydroxide (guanidine residues);

b) Weber Reagent (it is oxidized by sodium nitroprusside Na[Fe(CN)5NO]+K3[Fe(CN)6]+NaOH) – red colour (guanidine residues);

c) Brown colour with basic potassium tetraiodomerrcurate (Nernst reagent) and red sediment with copper-tartrate reagent– Feling reagent; “silver mirror” reaction (on aldehyde group);

d) Condensation with phenols in the presence of concentrated sulfuric acid – aurine dye;

e) On the aldehyde group of streptos (with a hydrazine, a semicarbazide – white sediments).

Aurine dye red colour

Assay• Microbiological method (UP).• Photocolorymetry which is based on the Maltol test.• Cerimetry. Titrant – Cerium sulfate. Indicator – iron (III)

chloride. Em = М. м./2

Ce4++ 1e

1

2Ce3+

O

OH

CH3

O

O

O

CH3

O

- 2e + 2H+

Storage In the dry place.

Application Broad-spectrum antibiotic. Antituberculosis

drug. At the treatment of pneumonia, peritonitis, honorrh(o)ea, brucellosis.

Produced in bottles, sealed with rubber stoppers with crimped aluminum caps on 0,25, 0,5 and 1,0 of the active substance in terms of streptomycin-base.

Inject inner muscular 0,5-1,0 g on a day. Side effects. Kidney-and oto-toxic, respiratory

depression, is rapidly developing resistance (2-3 days).

Aminoglycosides Aminoglycosides The general formulaThe general formula

CharacteristicCharacteristic. . According to the physical properties aminoglicosides antibiotics are powders of white, yellow or creams colors, hydroscopic. Freely soluble in water and practically insoluble or low soluble in the most organic solvents. Optically active .

Kanamycin monosulfate (UP) (Kanamycini monosulfas)

• Composition of Kanamycin is aglucone 2-deoxystreptomine (meso-1,3-diamino-4,5,6-trioxycyclohexan) and two saccharates - 3-amino-3-deoxy-D-glucose and 6-аmino-6-deoxy-D-glucose.

• Drug is obtained by the fermentation of Streptomyces kanamycetis at 27-29 оС and рН=7, the environment that contains starch and soy flour. From the environment Kanamycin A, B and C is extracted by an ionchangers.The list toxic Kanamycin A has, that’s why it composes the mass of the drug Kanamycin monosulfate (94 %).

• The semi-synthetic analog of Kanamycin is amikacin sulfate. Its main difference from kanamycin is a present of 4-аmino-L-2-oxybtyl radical. Except aglucone 2- deoxy-D-streptamine amikacin has 2-deoxy-L-streptamine.

Amykacin сульфат (Amyсаcini sulfas)

O OH

OH

NH2

CH2OH

O

HN

NH2

OH

O

O

OH

OH

OH

CH2NH2

* 2 H2SO4

C

O

CH

OH

CH2

CH2

NH2

• Neomycin like Kanamycin is a mixture of two stereoisomers В and С. Aglucone – 2-deoxystreptamine ties three saccharides.

• The drug is obtained from the liquid Streptomyces fradiae culture by the carboxylic cation exchange resins. In 1949 neomycin was the first obtained by Waxman and le Shatelye.

• Monomycin sulfate drug is a mixture of monomycins that are produced by Actinomyces circulatus var. monomicini. The difference of the monomycin chemical structure from neomycin is a present in 6’ position – СН2ОН group (paramosa) exept – CH2NH2.

• Gentamycn is similar to kanamycin. It is a metabolizing product of Micromonospora purpurea. It is a mixture of:

Neomycin sulfate (Neomycini sulfas)

Monomycin sulfate (Monomycini sulfas)

O

OH

NH2

OH

H2C OH

O

NH2

OH NH2

OCH2

OH

O

O

HOO

OH

NH2

OH

CH2H2N*nH2SO4

Gentamycin sulfate (Gentamycini sulfas)

Aminoglycoside’s identificationAminoglycoside’s identification

Physical constantsPhysical constants: : melting temperaturemelting temperature, , UVUV- - and and Proton Nuclear Magnetic Resonanse--spectroscopyspectroscopy, , TLCTLC, , Liquid Liquid chromatographychromatography..Reaction on the aliphatic amino-group of Kanamycin Reaction on the aliphatic amino-group of Kanamycin monosulfatemonosulfate – – at the heating with a ninhudrin solution at the heating with a ninhudrin solution observed violet color. observed violet color. Melting temperature of Kanamycin picrateMelting temperature of Kanamycin picrate..They give reaction of sulfateThey give reaction of sulfate..Bial’s reaction Bial’s reaction ((pentos openningpentos openning). ). For the indentification For the indentification of Kanamycin monosulfate and neomycin sulfate using a of Kanamycin monosulfate and neomycin sulfate using a color reaction with a alcohol solution of an orcyn color reaction with a alcohol solution of an orcyn (methyl(methylresorcinol) and concentrated hydrochloric acid at resorcinol) and concentrated hydrochloric acid at the present of iron (III) chloridethe present of iron (III) chloride. . Solution gets green Solution gets green colourcolour..

After acidic hydrolysis kanamycin and amikacin give the reaction of After acidic hydrolysis kanamycin and amikacin give the reaction of the reducing saccharidesthe reducing saccharides ( (Feling reagentFeling reagent. . NernstNernst, , TolensTolens).).

Amykacin according to the amide group forms color complexes with Amykacin according to the amide group forms color complexes with the hard metal’s saltsthe hard metal’s salts ( (reaction with cobalt nitrate after sodium reaction with cobalt nitrate after sodium

hydroxide hydroxide neutralizationneutralization – – violetviolet). ).

Amikacin at the heating with concentrated mineral acids forms from Amikacin at the heating with concentrated mineral acids forms from the saccharidesthe saccharides 5- 5-aminomethylfurfuralaminomethylfurfural, , which gives the colour which gives the colour reaction with antronreaction with antron::

AssayAssayMicrobiological methodMicrobiological method ( (UPUP).).

PolarimetryPolarimetry ( (gentamycin sulfategentamycin sulfate).).

PhotocolorimetryPhotocolorimetry..

Absorption spectroscopy inAbsorption spectroscopy in UVUV- - and visible regionand visible region. .

StorageStorage Protection from lightProtection from light. .

ApplicationApplication Broad spectrum antibioticsBroad spectrum antibiotics. . FFor the treatment of the or the treatment of the

gastrointestinal tract diseases, tuberculosis and infectious gastrointestinal tract diseases, tuberculosis and infectious skin diseases, sepsis, urinary tract infectionsskin diseases, sepsis, urinary tract infections. .

Kanamycin monosulfateKanamycin monosulfate – – bottlebottle onon 0,5 0,5 andand 1,0 1,0 gg. . Inner muscular injectionInner muscular injection 5-7 5-7 daysdays. . HH..dd..dd. – 2 . – 2 gg

Gentamycin sulfateGentamycin sulfate – – Solution for injectionSolution for injection.: .: exports exports producingproducing. 40 . 40 oror 80 80 mgmg 2,0 2,0 mlml №10; №10; national (Ukrainian) national (Ukrainian) producingproducing 4% 1,0 4% 1,0 oror 2,0 2,0 mlml №10; №10; creamcream 0,1% 15 г; 0,1% 15 г; eye eye oinmentoinment 0,3% 5,0 0,3% 5,0 gg. . Average day’s doseAverage day’s dose – 3 – 3 mgmg//kg,kg, 2-3 2-3 times, inner muscular injectiontimes, inner muscular injection..

AmykacinAmykacin – КМ – – КМ – bottlebottle on on 0,1 0,1 andand 0,25 0,25 gg. . Average Average day’s doseday’s dose 15 15 mgmg//kg by 2 times inner muscular injectionskg by 2 times inner muscular injections..

TergynanTergynan – – vaginal tabletsvaginal tablets ((ternidazoleternidazole, , neomycin neomycin sulfatesulfate, , nnystatin ystatin , , prednisoloneprednisolone).).

Side effectsSide effects – – Kidney-and oto-toxic actionKidney-and oto-toxic action, , allergy allergy and and othersothers..

Lincomycins In medical practical using Lincomycin hydrochloride and

clindamycin

Lincomycin hydrochloride (Lyncomycini hydrochloridum) (UP)

Monohydrate methyl-6,8-dideoxy-6-[(2S,4R)-1-ethyl-4-propyl-pyrrolidinyl-2-carboxamido]-1-thio-D-erythro-α-D-galacto-octopyranoside hydrochloride

OOH

SCH3

OH

OH

C HNH

C

C

H

CH3

HO

O

N

CH3

C3H7

* HCl * H2O

• Lincomycin hydrochloride– used at sepsis, staphylococ infections, acute and chronic osteomyelitis, purulent skin infections, otitis. Externally at purulent diseases of skin and soft tissue. Intravenous, inner muscular injection. Once dose - 0,5 g, day dose – 1,5 g. Capsules on 0,25 g №20; solution for injection 30% 1,0 ro 2,0 № 10.

Contraindications – severe liver and kidney disease, myasthenia gravis.

Clindamycin (Dalacin) – broad-spectrum ANT. Capsule on 150 and 300 mg № 16; solution for injection 150 mg/ml 2,0 or 4,0 № 1; vaginal cream and suppositories.

Macrolides antibiotics They contain a lactone ring with 12-17 carbon atoms, it

ties with amino carbohydrates (for the amino glycosides type) and neutral sugars. Reserve antibiotics.

Modern classification1. 14 – members: natural (erythromycin, oleandomycin);

prodrug (esther and erythromycin salts, oleandomycin esthers); semi-synthetic (roxithromycin, clarithromycin, dirithromycin, josamycin, its active metabolite is 14-hydroxi clarithromycin).

2. 15 – members: semi-synthetic (additional nitrogen atom – azalides - azithromycin (sumamed)

3. 16 – members: natural (spiramycin (rovamycin), midecamycin (macropen), semi-synthetic (midecamycin acetate (miocamycin).

It is now known about 100 macrolide antibiotics, the general formula:

In medical practice the most often used :

1. Erythromycin phosphate (altrocin –S);

2. Spiramycin (rovamycin, rovalen);

3. Midecamycin(macropen);

4. Roxithromycin (roxide, rulid, renicin, rovenal);

5. Josamycin (wilprafen );

6. Clarithromycin (fromilid , klabax , clacid );

7. Azithromycin (Azitrox, Azithro, Zithromax , sumamed ).

Erythromycin(Erythromycinum)

• Erythromycin is produced from a strain of the actinomycete Saccharopolyspora erythraea. .

• Erythromycin consists of aglucone erythrolide (14-members lactone) and two sugars: cladynos (3-methyl-3-methoxy-2,6-didedeoxyhexopyranos) and deamine (pycrocin, 3- dimethylamino-4,6- didedeoxyhexopyranos). Cladynos splits off at the interaction with eryehromycin with 0,5 М НСl solution at the cold, and deamine – at the interaction with eryehromycin with 6 М НСl solution.

• Erythromycin – white crystalline substance bitter on taste, melting at 190-193 оС, soluble in water, freely soluble in ethanol, acetone and chloroform.

With concentrated H2SO4 gives red-brown color, аnd with concentrated HCl – orange color, that transfers into red after puple.

• 1mg of Erythromycin equals 1000 U.A.

Oleandomycin phosphateOleandomycini phosphas

OCH3

H3C

CH3

OH

CH3

CH3

O O

CH3

O

O

OO

CH3

OH

OCH3

H3C

N

H3C

H3COH

H2C

O

*H3PO4

Azithromycin (UP) (Azithromycinum)

• Identification: IR-spectroscopy

• Assay:

Liquid chromotography

O

N

CH3OH

H3C

H3C

CH3

OH

CH3 CH3

O O

CH3

H3C

OOH

OO

CH3

OH

CH3

H3C

N

HO H3CO

H3C

H3C

• Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, and injections.

• Erythromycin tablets on 100000 and 250000 U.A. are used for the treatment of pneumonia, scarlatina , angina, anthrax etc. For the local using at the infection wounds, burns, trophic exulcerates, trachoma, bedsores there is recommended an ointment Unguentum erythromycini, its 1 g contains 10000 U.A.

• Other antibiotics-macrolides are produced as oral medicine forms.

• Macrolide antibiotics are used by prescription, determine the sensitivity to this group and compared with a sensitivity to other groups as well as macrolides quickly develop resistance. If antibiotics- macrolides are not used continuously, the sensitivity of the microorganism to them restored.

AnsamycinAnsamycin’s antibiotics’s antibiotics At the core of the structure is aromatic ring, coupled with At the core of the structure is aromatic ring, coupled with macrocyclic aliphatic chain, called Anza-chain. Aliphatic macrocyclic aliphatic chain, called Anza-chain. Aliphatic chain does not contain the lactone bonds that are typical for chain does not contain the lactone bonds that are typical for macrolide’s antibiotics, it attaches to the core with the macrolide’s antibiotics, it attaches to the core with the amide nitrogen atom.amide nitrogen atom. The following antibioticsThe following antibiotics belong tbelong to ansamycino ansamycin’s ’s : rifampicin, : rifampicin, streptovaricin, tolipomicin, galomicin, naphtomicin etc.streptovaricin, tolipomicin, galomicin, naphtomicin etc. Rifampicin and its semi-synthetic analogs are used as medicines [Rifampicin and its semi-synthetic analogs are used as medicines [3-3-(4-(4-methylmethyl-1--1-piperazinpiperazinyliminomethylyliminomethyl)- )- rifampicin ]rifampicin ], , rrifabutinifabutin , , rifampitin and the combine drugsrifampitin and the combine drugs..AnsamycinAnsamycin’s antibiotics’s antibiotics have broud-spectrum action and a high have broud-spectrum action and a high efficiency.efficiency. Prescribed in the cases where other antibiotics are Prescribed in the cases where other antibiotics are ineffective. Used for the treatment of all forms of tuberculosis, ineffective. Used for the treatment of all forms of tuberculosis, diseases of gastrointestinal tract and pyogenic infections on the doses diseases of gastrointestinal tract and pyogenic infections on the doses of 0,3-0,45 g.of 0,3-0,45 g.Microorganisms very quick develop the resistance to Rifampicin.Microorganisms very quick develop the resistance to Rifampicin.

Rifampicin’s general formula and radicals

Polyenes antibioticsPolyenes antibiotics Polyenes aPolyenes antibiotics ntibiotics have an have an antifungal activity. Thantifungal activity. Theyey are are mixturemixturess of of substances that are very close in structure. Molecule of each substances that are very close in structure. Molecule of each component consists of the aglycone having macrocyclic structure, and component consists of the aglycone having macrocyclic structure, and amino sugars, connected by a glycosidic bond. Polyene structure of amino sugars, connected by a glycosidic bond. Polyene structure of the aglycone has the aglycone has 6-76-7 double bonds and 35-40 carbon atoms. double bonds and 35-40 carbon atoms.

In medical practice the following medicines usedIn medical practice the following medicines used: : nystatinnystatin, , Amphotericin В, В, levorinlevorin, , trihmicintrihmicin, , candocidincandocidin, , mmycoheptinycoheptin

, , ggriseofulvin riseofulvin , , aamphoglucamin mphoglucamin , , etcetc..ApplicationApplication. . For the treatment of candidiasis, dermatomycoses, For the treatment of candidiasis, dermatomycoses, trichomoniasis, fungal diseases.trichomoniasis, fungal diseases.

The modern antifungal medicinesThe modern antifungal medicines – – imidazole derivativesimidazole derivatives: : KetoconazoleKetoconazole (1-2%), (1-2%), Oxiconazole Oxiconazole ((mifungarmifungar), ), IntraconazoleIntraconazole ((orungalorungal); ); allylamineallylamine: : TerbinafineTerbinafine ((lamisillamisil, , terbisilterbisil, , exifineexifine); ); triazol derivativestriazol derivatives : : FluconazoleFluconazole ((diflucandiflucan, , micosystmicosyst).).

Nystatin Nystatinum

tablets, ointment , suppository

• Griseofulvin

Griseofulvinum

tablets, liniment O

O

Cl

OCH3

H3CO

OCH3

O

CH3

CH3

O OH OH OH O

O

OH

OH

OH

COOH

OH

H3C

HO

H3C

O

O

OH NH2

CH3

OH

Nystatin (Nystatinum) (UP)

• Identification: UV-, ІR-spectroscopy; Substance + concentrated hydrochloric acid – brown

color;Substance + concentrated sulfuric acid – brown color

that transfers into a violet;Liquid chromatography.• Assay:Microbiological method• For a substance that is designed to produce medicines

for oral use must be withstanded the test on abnormal toxicity.

Amphotericin ВAmphotericinum B

amphomin, amphotret, fungizome, fungizone

• Yellow or yellow-orange powder. Hygroscopic . Sensitive to the action of light and temperature. It is easy inactivated in acid and base medium.

• Application - systemic and deep mycoses (blastomycosis, criptococoz), mold mycosis, chronic and granulomatous forms of candidiasis.

Intravenous injection, inhalation and topical (cream). Used only in hospital settings: a highly toxic drug, capable to cumulation, kidney throtoxic, causes the reducing of potassium quantity in a blood.

CH3O OH OH O

O

OH

OH

COOH

OH

H3C

HO

H3C

O

O

OH NH2

CH3

OH

OH

OH

Polypeptides antibioticsPolypeptides antibiotics Polypeptides antibiotics according to their amino acids composition, chemical structure are different from other peptides (proteins). Amino acids from other peptides (proteins). Amino acids associate associate in a cyclein a cycle..In medical practice the following medicines used: In medical practice the following medicines used: GramicidinGramicidin SS, , Polymyxin M Polymyxin M ..StorageStorage. . Protection from light.ApplicationApplication. . According to a high toxicty of polypeptides the are According to a high toxicty of polypeptides the are applied outside, at the internal using they cause applied outside, at the internal using they cause hemolysis hemolysis of of erythrocyteerythrocytes. At the heavy septic and gastroenteric diseases (as s. At the heavy septic and gastroenteric diseases (as enemas), when other antibiotics are uneffective, for washing of enemas), when other antibiotics are uneffective, for washing of purulent woundpurulent wounds, ulcers, bedsores, rinse of throat. s, ulcers, bedsores, rinse of throat. GramicidinGramicidin SS has the has the spermocidspermocidic action (as paste).ic action (as paste).GramidinGramidin ( (tablet fro tablet fro resorbresorb) – ) – GramicidinGramicidin SS 1,5 1,5 mgmg and and lidocainelidocaine h/chh/ch 10 10 mgmg.. SofradexSofradex ( (drops eye/earsdrops eye/ears) – ) – ggramicidinramicidin 0,05 0,05 mgmg, , neomycinneomycin 5,0 5,0 mgmg, , Dexamethason Dexamethason 0,5 0,5 mgmg. .

GramicidinGramicidin SS ((Gramicidin S)Gramicidin S)

GramicidinGramicidin SS is produced from a is produced from a bacterial bacterial strain of the strain of the Bacillus brevisBacillus brevis, , which are in the soilwhich are in the soil. . The first it was obtained in The first it was obtained in USAUSA. .

Antineoplastic antibioticsAntineoplastic antibiotics

InIn 1940 1940 actinomycinactinomycin was obtained by the american was obtained by the american scientist scientist WaxmanWaxman,, and in and in 1952 1952 there was determined the there was determined the antineoplastic action of the substanceantineoplastic action of the substance. . Antitumor antibiotics that are used in medical practice can Antitumor antibiotics that are used in medical practice can be divided into derivatives:be divided into derivatives:

tetracyclinetetracycline (doxorubicin(doxorubicin hydrochloridhydrochloridee););Aurelic acidAurelic acid ( (olivomycinolivomycin););Anthracycline (rubomycin);QuinolineQuinoline-5,8--5,8-diondion ( (Вruneomycin Вruneomycin ).).

For the analysis of these drugs physical, physical-chemical For the analysis of these drugs physical, physical-chemical and chemical methods are usedand chemical methods are used..StorageStorage. . In a well stoppered container in a dry place, protected from light at room temperature.

Doxorubicin hydrochloride(UP)Doxorubicini hydrochloridumAdriblastin

• Crystalline orange-red powder. Hygroscopic.

• Identifiction: ІR-spectroscopy, gives the reaction of chloride ions.

• Assay:

Liquid chromatography

O

O

OCH3

OH

OHH

OH

OH

O

O

OH

O

NH2

CH3

* HCl

Olivomycin А

O OH

OOH OH

OCH3 OH

CH3

O

O

O

CH3

C

O

H3C

O O

OCH3

OH

O OH

CH3

O

O

O

O

CH3

CH3

OH

O OH

CH3

C O

CH

CH3H3C

O

• Rubomycin hydrochloride

• Вruneomycin

O

O

COCH3

OCH3 OH

OH

O

OH

O

NH2OH

H3C

*HCl

N

N

O

O

OCH3

H3CO

COOH

CH3

OH

OCH3

H2N

H2N

OlivomycinOlivomycin А А – – yellow powder with a green tintyellow powder with a green tint. . HHygroscopicygroscopic. Freely soluble in water, alcohol, practically . Freely soluble in water, alcohol, practically insoluble in insoluble in chloroformchloroform, ether, ether. . Storage as a toxic substance Storage as a toxic substance at belowat below 20 20 ооС. С. Using intravenous injection or localUsing intravenous injection or local ((oinmantoinmant). ). ВruneomycinВruneomycin ((streptonigrinstreptonigrin) – ) – brown brown crystalline crystalline powderpowder. . Practically insoluble in water, alcohol, soluble in DMFAPractically insoluble in water, alcohol, soluble in DMFA, , pyridinepyridine. . Storage as a toxic substance at belowStorage as a toxic substance at below 20 20 ооС С in a in a dark placedark place. . Using intravenous injection as a sodium saltUsing intravenous injection as a sodium salt, , hypodermic injectionhypodermic injection – – necrosisnecrosis. . Rubomycin hh/ch/ch – – red powder red powder. . HHygroscopicygroscopic. Freely . Freely soluble in water, alcoholsoluble in water, alcohol, , slightly soluble in slightly soluble in chloroformchloroform. . The color of medicine in acidic mediumThe color of medicine in acidic medium– – redred, , in basicin basic – – blueblue. . Storage as a toxic substance at belowStorage as a toxic substance at below 20 20 ооС. С. Using Using intravenous injection, inner muscular injection or intravenous injection, inner muscular injection or hypodermic injectionhypodermic injection – – necrosisnecrosis. .

6 – 6 – Fluoroquinolones Antibiotics of a 4-quinoline derivatives, which in the 6-th Antibiotics of a 4-quinoline derivatives, which in the 6-th

position contain Fluorine atomposition contain Fluorine atom, , and in the 7-th position -and in the 7-th position - piperazine piperazine cyclecycle. .

Their Their precursorprecursors such as derivatives of quinoline and s such as derivatives of quinoline and naphtiridinnaphtiridin, , are started to use in are started to use in 6060 years of years of ХХ ХХ centurycentury. . The first The first representative representative of this class is nalidyxone acidof this class is nalidyxone acid ( (nevigramonnevigramon,, negram negram) ) and its analogs is a pipemand its analogs is a pipemііdine aciddine acid ( (pipemidinepipemidine, , palinpalin, , urosepturosept, , pimidelpimidel). ). These drugs are characterized primarily by the activity to These drugs are characterized primarily by the activity to gram-negative microorganisms, the rapid development of resistance gram-negative microorganisms, the rapid development of resistance to these antibiotics causing their using only for infectious diseases to these antibiotics causing their using only for infectious diseases of the urinary tract.of the urinary tract.

Nalidyxone acidNalidyxone acid

(belongs to naphtiridines):

Fluoroquinolones began to be introduced into medical practice in 80 years of the last century. Introduction of fluorine atoms in the molecule of quinoline derivatives and naphtiridinnaphtiridin leds to a group of drugs with fundamentally new pharmacological properties. Fluoroquinolones are a highly active antimicrobial compounds, which are used at severe infections of the different etiology and localization (respiratory tract infections, skin and soft tissues, bones and joints, gastrointestinal tract, postoperative infections, other chronic inflammatory processes).            The mechanism of fluoroquinolones action: they affect on the metabolism of bacterial DNA by inhibiting the enzyme in bacterial cells, DNA gyrase, which controls the structure and function of DNA. Inhibition of DNA gyrase leads to destruction of the bacteria (bactericidal effect). Antibacterial activity of quinolones is also connected with the effect on RNA synthesis of bacteria and bacterial proteins, the stability of membranes and other vital processes of the bacterial cells.

Quinolones have a high effect on aerobic gram-negative bacteria and have little effect on anaerobic bacteria. They are rapidly absorbed from the gastrointestinal tract and are effective at the inside administration.            Quinolones inhibit the oxidazing enzymes of liver and can increase the effects of drugs (increase the side effects of theophylline).            The quinolones activity increases when administered in their molecules of two (lomefloxacin) or three (hemafloxacin) fluorine atoms.            Replacement of the ethyl radical in norfloxacin on cyclopropyl leads to the increasing of the substances activity (ciprofloxacin) by 3-8 times.            Some drugs of this group after extensive clinical using have been banned because of serious side effects.

Fluoroquinolones classificationThe first generationThe first generation

PefloxacinPefloxacin ( (AbactalAbactal, , UnikpefUnikpef, , PefloxPeflox-400);-400);Norfloxacin Norfloxacin ( (Norbactin,Norbactin, NegafloxNegaflox, , NalicinNalicin, , NoriletNorilet, , RenorRenor) ) is is the the

active metabolite of pefloxacinactive metabolite of pefloxacin

The second generationThe second generationCiprofloxacin Ciprofloxacin ((CiprinolCiprinol, , CiprobayCiprobay, , CyprohexalCyprohexal, , CyproletCyprolet, , CyfranCyfran,,

CipromCiprom, , CipronatCipronat););Ofloxacin Ofloxacin ((ZinocinZinocin, , OflohexalOflohexal, , OfloxinOfloxin, , GeofloxGeoflox, , ZanocinZanocin, , ZofloxZoflox, ,

TarivilTarivil,);,);LomefloxacinLomefloxacin ( (LomaleyLomaley, , MaxacvinMaxacvin,, lomflox lomflox, , OxacinOxacin))

The third generationThe third generationLevofloxacinLevofloxacin ( (LocsofLocsof, , TavanicTavanic, , LefloxLeflox) – ) – left rotation isomer of left rotation isomer of

ofloxacinofloxacin;;MoxifloxacinMoxifloxacin ( (AveloxAvelox););GatifloxacinGatifloxacin ( (ZicvinZicvin, , TerbisTerbis););SparfloxacinSparfloxacin ( (OmnifloxOmniflox).).

• Norfloxacin

Norfloxacinum

1-ethyl-6-fluor-1,4-dihydro-4-оxо-7-(1’-piperazinyl)-3-

quinolinecarboxylic acid

• OfloxacinOfloxacinum

(±) 3-methyl- 7-оxo-9-fluor-10-(4’-methyl-1’- piperazinyl)-2,3-

dihydro-7Н-pirido-1,4-benzoxazine -6- carboxylic

acid

N

F

NHN

O

COOH

C2H5

N

F

NN

O

COOH

H3C

OCH3

• Ciprofloxacin h/ch (UP 1.2)

Ciprofloxacini hydrochloridum

1-cyclopropyl-6-fluorine-4-оxo-7-(piperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acid

hydrochloride

• Lomefloxacin

Lomefloxacinum

1-ethyl-6,8-difluorine-7-(3’-methyl-1’- piperazinyl)-4-

оxo-1,4-dihydro-3-quinolinecarboxylic acid

N

F

NHN

O

COOH

CH

H2C CH2

* HCl * H2O

N

F

NHN

O

COOH

C2H5

H3C

F

FluoroquinolonesFluoroquinolones characterscharacters Pale yellow crystalline powder, norfloxacin and

ciprofloxacin - hygroscopic. Very slightly or practically insoluble in water, soluble in alcohol and acetone. Norfloxacin is a photosensitive. Chlorides of ofloxacin and ciprofloxacin are soluble in water and practically insoluble in alcohol, acetone and methylene chloride.

Fluoroquinolones identificationIR, UV spectroscopy, TLC.Heterocyclic nitrogen atom is determined by Dragendorff’s

reagent, picric acid.Oxo-group is identified by the reactions of the formation of oxime’s precipitation (reaction with hydroxylamine), thiosemicarbazone (reaction with thiosemicarbazide) phenylhydrazone (reaction with phenylhydrazine).

Chlorides containing salts give the reaction of chloride.Chlorides containing salts give the reaction of chloride.

Formation of the chelate complexes of a dark-red Formation of the chelate complexes of a dark-red color with color with FeFe3+3+ ionsions::

For the determining of fluorine atom the mineralization For the determining of fluorine atom the mineralization is carried out in order to obtain the Fis carried out in order to obtain the F - - ion, ion, a) after pre-mineralization with a mixture for sintering. a) after pre-mineralization with a mixture for sintering. The residue was dissolved at pH 4,0-5,0, to add a The residue was dissolved at pH 4,0-5,0, to add a solution of calcium chloride, observed opalescence solution of calcium chloride, observed opalescence (precipitate CaF(precipitate CaF22):): 22FF-- + Ca + Ca2+2+ → CaF→ CaF22↓↓

bb) ) AAfter the combustion with oxygen in the presence of hydrogen fter the combustion with oxygen in the presence of hydrogen peroxide. Fluorides are formed discolor red solution of iron peroxide. Fluorides are formed discolor red solution of iron (III) thiocyanate:(III) thiocyanate:

Fe(SCN)Fe(SCN)6 6 + 6F+ 6F-- → [FeF → [FeF66]]3-3- + 3(SCN) + 3(SCN)--

b) b) after the mineralization of the substance under the influence of after the mineralization of the substance under the influence of molten sodium metal. Fluorides destroy the zirconium-alizarin molten sodium metal. Fluorides destroy the zirconium-alizarin red complex, according to that extract a free alizarin is a red complex, according to that extract a free alizarin is a yellow color:yellow color:

Extracted at this case a white precipitate zirconium (IV) fluoride is Extracted at this case a white precipitate zirconium (IV) fluoride is dissolved at the same time in excess of fluoride with the formation dissolved at the same time in excess of fluoride with the formation of a colorless anionof a colorless anion [ZrF[ZrF66]]2-2-..

AssayAssay 1. 1. Atsidimetry in a non-aqueous medium, a Atsidimetry in a non-aqueous medium, a

direct titrationdirect titration. Е. Емм=М.м.=М.м.2. 2. Hydrogen chloride Hydrogen chloride salts are determined by a liquid salts are determined by a liquid

chromatographychromatography ..

StorageStorageProtection from lightProtection from light..

Side effectsSide effects;;

Fluoroquinolones cause photosensibilization cause photosensibilization (sensitivity to light), so we can not at the time of (sensitivity to light), so we can not at the time of acceptance of this group of drugs irradiate with UV-acceptance of this group of drugs irradiate with UV-and sunlight.and sunlight.Accumulation in the skeletal system - can not use for Accumulation in the skeletal system - can not use for children under 15 years old, pregnant, during children under 15 years old, pregnant, during lactation.lactation.

ProducingProducing;;PefloxacinPefloxacin– – tabl.tabl. onon 04 04 gg; ; ampullaampulla onon 5 5 mlml (0,4 (0,4gg).).Norfloxacin Norfloxacin andand LomefloxacinLomefloxacin – – tabl.tabl. onon 0,4 0,4 gg..OfloxacinOfloxacin – – tabl on tabl on 0,2 0,2 gg..CiprofloxacinCiprofloxacin – – tabl. ontabl. on 0,25 0,25 gg; 0,5 ; 0,5 gg; 0,75 ; 0,75 gg; 0,2% ; 0,2% solution solution

for infusion on for infusion on 50, 100 50, 100 mlml; 1% ; 1% solution for injection solution for injection ааmpullampulla 10 10 mlml. . Eye-ear dropsEye-ear drops 0,3%. 0,3%. CifranCifran SSТ – Т – ciprofloxacinciprofloxacin 500 500 mgmg + + tinidazole tinidazole 600 600 mgmg..

LevofloxacinLevofloxacin – – tabltabl. 0,25 . 0,25 gg; 0,5; 0,5gg №5; №5; solution for infusionsolution for infusion 0,5 0,5 gg onon 100 100 mlml №1. №1.

MoxifloxacinMoxifloxacin – – tabltabl. 0,4 . 0,4 gg №5; №5; solution for infusionsolution for infusion 0,4 0,4 gg on on 250 250 mlml №1. №1.

GatifloxacinGatifloxacin – – tabltabl. 0,2 . 0,2 andand 0,4 0,4 gg №10; №10; solution for infusionsolution for infusion 0,4 0,4 gg onon 200 200 mlml №1. №1.

SparfloxacinSparfloxacin - - tabltabl. 0,2 . 0,2 gg №10. №10.

Thanx for Thanx for attentionattention