الفهرس 
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Abstract
1,8-naphthyridone and 1,3,4-oxadiazole skeletons have been known for their antimicrobial activity. The strategy of the work is concerned with the synthesis of a new series of hybrid compounds containing both 1,8-naphthyridone and thiosemicarbazide/1,3,4-oxadiazole moiety, followed by biological evaluation of these compounds for their antimicrobial activity. Analogous series of brominated compounds was synthesized to test the effect of bromination on antimicrobial activity of 1,8- naphthyridone. The synthesis of the target compounds started with nalidixic acid and necessitates the preparation of the following intermediates: Methyl 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (II) Methyl 6-bromo-1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3- carboxylate (III) 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrazide (V) 6-Bromo-1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrazide (VI) The following target compounds (VII-XIV) were synthesized: 6-Bromo-1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (IV) 2-(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl) hydrazinecarbothioamide (VII) 2-(6-Bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3- carbonyl)hydrazinecarbothioamide (VIII) 2-(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-Nphenylhydrazinecarbothioamide (IXa) 2-(6-Bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-Nphenylhydrazinecarbothioamide (Xa) N-(4-chlorophenyl)-2-(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3- carbonyl)hydrazinecarbothioamide (IXb) 2-(6-Bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N- (4-chlorophenyl)hydrazinecarbothioamide (Xb) 2-(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N-(4- methylphenyl)hydrazinecarbothioamide (IXc) 2-(6-Bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N- (4-methylphenyl)hydrazinecarbothioamide (Xc) 2-(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N-(4- methoxyphenyl)hydrazinecarbothioamide (IXd) 2-(6-Bromo-1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N- (4-methoxyphenyl)hydrazinecarbothioamide (Xd) 3-(5-Amino-1,3,4-oxadiazol-2-yl)-1-ethyl-7-methyl-1,8-naphthyridin-4(1H)-one (XI) 3-(5-Amino-1,3,4-oxadiazol-2-yl)-6-bromo-1-ethyl-7-methyl-1,8-naphthyridin- 4(1H)-one (XII) 1-Ethyl-7-methyl-3-(5-(phenylamino)-1,3,4-oxadiazol-2-yl)-1,8-naphthyridin- 4(1H)-one (XIIIa) 6-Bromo-1-ethyl-7-methyl-3-(5-(phenylamino)-1,3,4-oxadiazol-2-yl)-1,8- naphthyridin-4(1H)-one (XIVa) 3-(5-((4-Chlorophenyl) amino)-1,3,4-oxadiazol-2-yl)-1-ethyl-7-methyl-1,8- naphthyridin-4(1H)-one (XIIIb) 6-Bromo-3-(5-((4-chlorophenyl) amino)-1,3,4-oxadiazol-2-yl)-1-ethyl-7-methyl- 1,8-naphthyridin-4(1H)-one (XIVb) 1-Ethyl-7-methyl-3-(5-(4-methylphenylamino)-1,3,4-oxadiazol-2-yl)-1,8- naphthyridin-4(1H)-one (XIIIc) 6-Bromo-1-ethyl-7-methyl-3-(5-(4-methylphenylamino)-1,3,4-oxadiazol-2-yl)-1,8- naphthyridin-4(1H)-one (XIVc) 1-Ethyl-3-(5-((4-methoxyphenyl) amino)-1,3,4-oxadiazol-2-yl)-7-methyl-1,8- naphthyridin-4(1H)-one (XIIId) 6-Bromo-1-ethyl-3-(5-((4-methoxyphenyl) amino)-1,3,4-oxadiazol-2-yl)-7-methyl- 1,8-naphthyridin-4(1H)-one (XIVd) The purity of the intermediates and the target compounds was ascertained by TLC and their structures were confirmed by spectral data (IR, 1H-NMR, 13C-NMR and MS) and elemental analyses. The synthesized compounds (II-XIV) were in vitro tested for their antibacterial activity against Staphylococcus aureus, and Bacillus cereus as examples of Grampositive bacteria; and Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa as examples of Gram-negative bacteria. The antitubercular activity was in vitro tested on Mycobacterium smegmatis. In general, most of the tested compounds showed comparable to higher activity in comparison with nalidixic acid. All compounds exhibited significantly higher activity than nalidixic acid against S. aureus with IXa, IXb, XIIIa and XIIIb possessing three times higher potency (~ 7 mM) than the parent drug, nalidixic acid (21.5 mM). In addition, S. aureus and B. cereus were the most susceptible bacteria by the compounds. The least affected bacterium was E. coli being inhibited by the target compounds in concentrations higher than nalidixic acid MIC. The activity against P. aeruginosa was exclusively characteristic to the thiosemicarbazide series (equipotent to twice of nalidixic acid), with Xd having the highest potency. Concerning antitubercular activity, the compounds bearing para-substituted phenyl, IXb, XIIIb, XIVb, IXc, XIIIc, XIVc, IXd and Xd, exhibited the highest activity. The results for antifungal activity screening revealed that only few of the target compounds possessed antifungal activity. Compounds XII, XIIIa and XIVa showed antifungal activity against C. albicans and compounds XIIIb, XIVb, XIIIc, XIVc, XIIId and XIVd showed antifungal activity against G. candidum. The effect of the structural modifications on the drug-likeness properties of the target compounds was also studied and revealed that these modifications resulted in derivatives that are in accordance with both Lipinski’s and Veber’s rules. Docking studies were performed using MOE software for in silico evaluation of the binding characteristics of the target compounds with bacterial gyrase cleavage complex, of three bacteria, in comparison with the co-crystallised quinolone as the reference ligand. The most active compounds showed the lowest dG values and their binding modes were consistent to that of the co-crystallized quinolones. On the other hand, the least active compounds showed higher dG values and lacked specifically the binding to the Mg-water bridge as well as the base stacking interactions.