1. LECTURE 10
Classification of heterocyclic compounds on the basis of their chemical structure. Derivatives of 5-nitrofuran as antimicrobial agents
associate prof. Mosula L.M.

2. The plan
1. Concept about heterocyclic compounds and their classification.
2. Derivatives of 5-nitrofuran as antimicrobial agents: Nitrofurazone, Nitrofurantoin, Furazolidone.

3. Concept about heterocyclic compounds and their types
Heterocyclic compounds are compounds, which contain cycles with atoms Carbon and other elements – heteroatoms (more often Оxygen, Nitrogen, Sulphur). Such compounds widespread in the nature (vitamins, antibiotics, enzymes, alkaloid) also can be easily synthesized. Heterocyclic compounds can contain cycles from three to six and more atoms and to contain odes of one to four heteroatoms, but the greatest practical value have five-and hexatomic heterocycles.

4. Trimonial heterocycles: Pentatomic heterocycles with one heteroatom:
Ethylene imine (aziridine) Ethylene oxide
Pentatomic heterocycles with one heteroatom:
furan pyrol thiophene

5. Pentatomic heterocycles with two heteroatoms:
pyrazol imidazole 1,3-thiazole 1,3-thiazolidin 1,3-oxazole

6. Pentatomic heterocycles with three and four heteroatoms:
1,2,3-oxadiazole
1,3,4-thiadiazole
1,2,4- thiadiazole
1,3,4-triazole
1,2,3,4-tetrazole

7. Condensed derivatives with pentatomic heterocycles:
benzofuran
benzimidazole
indole
purine

8. Feature of structure and chemical properties of pentatomic heterocycles
Furan is pentatomic heterocycle with one heteroatom – atom Oxygen:
Pentatomic heterocycles with one heteroatom (furan, pyrol, thiophene) have properties of aromatic compounds. -Position is most reactive. For its compounds characteristic are reactions of halogenation, alkylation, acylation, sulphonation, nitration.

9. Drugs –derivatives of furan
In medical practice use derivatives of 5-nitrofuran
Syntetical derivatives of 5-nitrofurfurol, which has substituens in position 2.
It is general formula of 5-nitroderivatives of furan series with bactericidal action.

10. Nitrofurazone (Nitrofural, Ph Eur monograph 1135) Nitrofuralum
Furacilinum
C6H6N4O4   198.1  
DEFINITION
Nitrofural contains not less than 97.0 per cent and not more than the equivalent of per cent of 2-[(5-nitrofuran-2-yl)methylene]diazanecarboxamide, calculated with reference to the dried substance.

11. Synthesis
Synthesis nitrofurazone (furacilinum) from furfurol (-furilaldehyde):
1. Furfurol nitration
furfurol nitrofurfuroldiacetate nitrofurfurol

12. *Acetylnitrate –is anhydride СН3СООН and HNO3:
2. Condensation 5-nitrofurfurol with semicarbazide hydrochloride.
5-nitrofurfurol semicarbazide hydrochloride semicarbazone 5-nitrofurfurol (nitrofural)
CHARACTERS
A yellow or brownish-yellow, crystalline powder, very slightly soluble in water, slightly soluble in alcohol.

13. IDENTIFICATION First identification B. Second identification A, C, D.
A. UV-spectroscopy.
B. Examine by infrared (IR) absorption spectrophotometry.
C. Examine by thin-layer chromatography.
D. Dissolve about 1 mg in 1 ml of dimethylformamide R and add 0.1 ml of alcoholic potassium hydroxide solution R. A violet-red colour is produced.

14. Other nitrofurans with alkali solutions yields too coloured products.
Other reactions:
1. With alkali solution.
Some crystals of drug add in flask, dissolutions in mix of 5 ml water R and 5 ml 10 % solution NaOH - orange-red colour are formed:
salt of nitronic acid
(orange-red colour)
Other nitrofurans with alkali solutions yields too coloured products.

15. 2. Melting point (230 С to 236 С). 3. Other colored reactions: №
At heating of salt of nitronic acid (product) allocated ammonia NH3 (smell and wet litmus paper becames blue colour in steam of boiling solution):
2. Melting point (230 С to 236 С).
3. Other colored reactions: №
Reagents
Result 1.
95 % ethanol, 10 % solution CuSO4, 10 % solution NaOH
Dark-red solution and precipitate 2.
Perhydrol (30 % solution Н2О2), 30 % solution NaOH
Light-yellow colour 3.
95 % ethanol, 5 % solution sodium nitroprusside Na2[Fe(CN)5NO]
Red solution and precipitate 4.
Nesler reagent (solution K2[HgI4] in KOH)
Red-brown colour

16. TESTS
pH (2.2.3)
To 1.0 g add 100 ml of carbon dioxide-free water R. Shake and filter. The pH of the filtrate is 5.0 to 7.0.
Loss on drying (2.2.32)
Not more than 0.5 per cent, determined on g by drying in an oven at °C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.

17. Antibacterial, topical antiprotozoan.
ASSAY
1. UV-spectrophotometry.
2. Iodometry, back titration (In the alkaline medium) .
I2 + 2NaOH → NaI + NaIO + H2O;
NaIO + NaI + H2SO4 → I2 + Na2SO4 + H2O,
I2 + 2Na2S2O3 → 2NaI + Na2S4O6.
Еm = М. м./4
STORAGE
Store protected from light (list of strong substance!).
Action and use
Antibacterial, topical antiprotozoan.
Ph Eur
Еm = М. м./4

18. Nitrofurantoin Furadoninum Furadantin Chemiofuran
General Notices
(Ph Eur monograph 0101)
Furadoninum
Furadantin
Chemiofuran
C8H6N4O5   238.2  
DEFINITION
Nitrofurantoin contains not less than 98.0 per cent and not more than the equivalent of per cent of 1-[[(5-nitrofuran-2-yl)methylene]amino]imidazolidine-2,4-dione, calculated with reference to the dried substance.

19. Synthesis
Synthesis of Nitrofurantoin (Furadoninum) from 5-nitrofurfurol:
5-nitrofurfurol 1-aminohydantoin Nitrofurantoin
CHARACTERS
A yellow, crystalline powder or yellow crystals, odourless or almost odourless, very slightly soluble in water and in alcohol, soluble in dimethylformamide.

20. IDENTIFICATION Other reaction:
A. UV-spectroscopy.
B. Reaction with alcoholic solution of alkali. Dissolve about 10 mg in 10 ml of dimethylformamide R. To 1 ml of the solution add 0.1 ml of 0.5 M alcoholic potassium hydroxide. A brown colour develops.
Other reaction:
1. SP Х. Reaction with water solution of alkali.
Some crystals of drug add in flask, dissolutions in mix of 5 ml water R and 5 ml 30 % solution NaOH - dark-red colour develops:

21. ASSAY 1. UV-spectrophotometry. 2. Alkalimetry, non-aqueous titration
TESTS
Loss on drying (2.2.32)
Not more than 1.0 per cent, determined on 1.00 g by drying in an oven at 100 °C to 105 °C.
Sulphated ash (2.4.14)
Not more than 0.1 per cent, determined on 1.0 g.
ASSAY
1. UV-spectrophotometry.
2. Alkalimetry, non-aqueous titration
Exact shot of drug dissolves in protophilic dissolvent (DMF, pyridine, butylamine) and titrate with standard solution of sodium methylate CH3ONa (or sodium methoxide, lithium methoxide – International Pharmacopoeia) in the presents DMF and dioxane (indicator – thymol dark blue).
Еm = М. м.

22. Nitrofurantoin Oral Suspension Nitrofurantoin Tablets
STORAGE
Store protected from light, at a temperature below 25 °C (list of strong substance!).
Ph Eur
Action and use
Antibacterial.
Preparations
Nitrofurantoin Oral Suspension
Nitrofurantoin Tablets

23. Furazolidone Diafurone Furoxon General Notices Furazolidonum
C8H7N3O5  225.2  
DEFINITION
Furazolidone is 3-(5-nitrofurfurylideneamino)oxazolidin-2-one. It contains not less than 97.0% and not more than 103.0% of C8H7N3O5, calculated with reference to the dried substance.

24. A yellow, crystalline powder.
Synthesis
Synthesis furazolidone from 5-nitrofurfurol by means of reaction condensation with 3-aminooxazolidone-2:
CHARACTERISTICS
A yellow, crystalline powder.
Very slightly soluble in water and in ethanol (96%); practically insoluble in ether .

25. IDENTIFICATION
 A. The infrared absorption spectrum.
B. With alcoholic solution of alkali. Dissolve 1 mg in 1 ml of dimethylformamide and add 0.05 ml of 1M ethanolic potassium hydroxide. A deep blue colour is produced.
Other reaction:
1. SP Х. With water solution of alkali.
Some crystals of drug add in flask, dissolutions in mix of 20 ml water R and 5 ml 30 % solution NaOH and heating - brown colour is produced.

26. TESTS Acidity or alkalinity
Shake 1 g for 15 minutes with 100 ml of carbon dioxide-free water and filter. The pH of the filtrate is 4.5 to 7.0,
Nitrofurfural diacetate
Carry out in subdued light the method for thin-layer chromatography. Any spot corresponding to nitrofurfural diacetate in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (2).
Loss on drying
When dried to constant weight at 105°, loses not more than 0.5% of its weight. Use 1 g.
Sulphated ash
Not more than 0.1%

27. Antibacterial; antifungal; antiprotozoal.
STORAGE
Furazolidone should be protected from light (list of strong substance!).
Action and use
Antibacterial; antifungal; antiprotozoal.

28. Thanks for attention!