About author :
Dept. of Pharmaceutical Chemistry
JNTUA-OTRI, Anantapur, India
A great number of drugs are heterocyclic compounds, mostly are of synthetic origin, few have obtained from natural resources which include alkaloids, xanthines, cardiac glycosides, vitamins and several antibiotics. Heterocyclic derivatives having two nitrogen atoms oriented in, 1-3 position are endowed with wide spectrum of biological activities. Imidazole have been drawn as promising structural units in the field of medicinal chemistry. Introduction of D-amino acids and N-methylation of amino acids like tyrosine, valine, alanine etc enhanced antimicrobial activity. Hence an attempt is made towards the sythesis of 5-nitroimidazolyl-benzoic acid derivative of N-methyl amino acids and peptide using solution phase technique of peptide synthesis. The synthesized amino acid derivatives studied for antimicrobial activity.
Key words: Thiazole, Coumarin, Quinoline, Furan, Imidazole, Valine, Alanine
Discovery of newer and more potent analogs of molecules with already established activities form a key part of research in the pharmaceutical field. A great number of drugs are heterocyclic compounds, mostly are of synthetic origin, few have obtained from natural resources which include alkaloids, xanthines, cardiac glycosides, vitamins and several antibiotics. Heterocyclic derivatives having two nitrogen atoms oriented in, 1-3 position are endowed with wide spectrum of biological activities. Nitroimidazole derivatives were developed not only because of their novelty to structure but also because of novelty to action.
Nitroimidazole derivatives such as metronidazole, tinidazole, nimorazole and ornidazole are clinically used as potent antiprotozoal drugs as well as antifungal agents. This effectiveness is due to the endogenous reduction reaction as an electron acceptor. Nitroimidazole have a wide spectrum of chemotherapeutic properties along with various side effects. When administered orally, nitroimidazoles derivatives show various side effects like hepatotoxicity, gastrointestinal disorder, skin rashes nausea, vomiting. Compound containing the imidazole ring are very important in living system, such as vitamin B12 and several pilocarpin alkaloids. Imidazole occurs in the essential amino acid histidine; histidines within enzymes are intimately involved in catalysis requiring protein transfer. 1-Histidine and its derivative carnosine which is a di-peptide and is a constituent of muscle.The Structurally related hormone, histamine is a vasodilator and is a major factor in allergic reaction such as hay fever. The synthesized compounds will be tested for their biological activities such as anti bacterial and antifungal activities.
General Method of Amino acid Synthesis:
The method involved in the synthesis of 4-[2′ – (5′-nitro)imidazolyl]benzoyl(NMe) amino acids is the coupling reaction between amino acid and 4-[2′-(5′-nitro) imidazolyl]benzoic acid
Protection of the Amino Group:
The tertiary butyloxycarbonyl (Boc-) group is one of the most widely used one. Boc- group has been used for amino protection because of its affordable cost and ease of availability. It satisfies all the requirements of selectively removable protecting groups. The Boc-amino acids were prepared by the following route.
Synthesis of N-methyl amino acids methyl ester:
Amino acids were converted into the corresponding methyl ester hydrochloride using thionyl chloride and methanol. The amino end was then protected by introducing Boc-group using ditertiary butylpyrocarbonate and triethylamine to get Boc-L-amino methyl ester. N-methylation of this compound was done by treating with methyl iodide and sodium hydride (Benoition method) to get Boc-(N-Me) amino methyl ester.
Preparation of 4-[2-(5-nitro)imidzolyl] benzoic acid :
A mixture of p-amino benzoic acid (34.25 gms, 250 mmol), dilute hydrochloric acid (15%, 120ml) and water (150ml) was heated to get a clear solution. The solution was cooled to RT and diazotized by the addition of sodium nitrite solution (30%, 48ml). The diazonium salt solution was filtered and to the filtrate, dilutes HCl (100ml) and nitroimidazole (250 mmol) and aqueous cupric chloride (5gms in 20ml of water) were added with stirring. Stirring was continued for 6 hrs and kept overnight in the refrigerator. The separated solid was collected by filtration and washed with water. The crude compound was crystallized from acetone to obtain pure of4 [2-(5-nitro)imidazolyl]benzoic acid.
Preparation of 4-[2‘-(5‘-nitro) imidazolyl]benzoyl(N-Me)-aminoacid
To the (N-Me) amino acid methylester(7.0 mmol.) THF (20ml), added 4-[2′-(5′-nitro) imidazolyl] benzoic acid acid (1.631gms, 7.0 mmol.), DIPC, Et3N (2.8ml) and stirred at room temp.for 24hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, residue was dissolved in CHCl3, washed with 10% NaHCO3 (10ml) and 5% HCl (10ml), dried over anhydrous Na2SO4 and evaporated under vacuum to get the title compounds. The crude product was recrystallized from CHCl3 & n–hexane.
Antibacterial studies of newly synthesized compounds showed moderate to good activity. However the N-methylated analogs have shown higher, antibacterial activity.
The enhanced activity of the N-methylated analogs is probably due to the presence of N-methyl group which strengthens the peptide bond, which is otherwise acid labile.
Antifungal studies of newly synthesized compounds showed potent activity by correlating with that fluconazole.The synthesized compounds may interfere with ergosterol biosynthesis by inhibiting demethylation at C14 of lanosterol there by causing accumulation of 1, 4-methylated sterols that disrupts the various sterol functions in the fungal cell. Comparison of SAR studies of imidazoles and various clinically available azoles showed that three structural features namely azole ring, unsubstantiated/substituted aromatic ring and a side chain are essential for fungicidal activity.
The new 4-[2′-(5′-nitro)imidazolyl] benzoyl(N-Me) amino acid derivatives was synthesized and characterized by physicochemical analytical data. Bythis studies find the structure-activity relationship and to optimize the structure. The synthesized amino acid derivative i.e., 4-[2′-(5′-Nitro) imidazolyl] benzoyl(N-Me) amino acid derivatives was confirmed by physicochemical & spectral analysis.