الفهرس 
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Abstract
The resistant of Acinetobacter baumannii to almost all the available anti-microbial agents and their susceptibility for the epidemic spread, made an urgent need for discovering new targets for inhibition of virulent Acinetobacter baumannii, without stimulation of other resistant. Long chain fatty acid (LCFA) pathway of A. baumannii is a vital factor for bacterial physiology, make it an attractive target for drug discovery. Ole1p (Δ9-fatty acid desaturase enzyme) is a key element in LCFA pathway. It responsible for converting saturated fatty acyl-CoA substrates to monounsaturated fatty acids which is critical for membrane permeability, biofilm formation and surface motility. In this study, the main aim is to design novel thiazol-2(3H)-imine derivatives targeting Ole1p. The design focused on exploration of the previously exposed SAR studies and bioisosteric modifications of the lead compounds. The structure and purity of each final synthesized compound were confirmed by X-ray crystallography, 1H-NMR, 13C- NMR, EI-MS, and elemental analysis.
Figure 1: Graphical abstract for the new synthesized compounds described in this work.
This study involves the synthesis of the following new compounds:
1) N-(3-Benzyl-4-hydroxy-4-methylthiazolidin-2-ylidene)acetamide (2)
2) 4-Methyl-3-(p-tolyl)thiazol-2(3H)-imine (5)
3) 5-Bromo-4-methyl-3-(p-tolyl)thiazol-2(3H)-imine (6)
4) 3-(o-Tolyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2(3H)-imine (9a)
5) 3-(p-Tolyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2(3H)-imine (9b)
6) 4-(2-Imino-4,5,6,7-tetrahydrobenzo[d]thiazol-3(2H)-yl)phenol (9c)
7) 3-(4-Chlorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2(3H)-imine (9d)
8) 3-Benzyl-2-imino-4-methyl-N-phenyl-2,3-dihydrothiazole--carboxamide (12a)
9) 3-(4-Hydroxyphenyl)-2-imino-4-methyl-N-phenyl-2,3-dihydrothiazole-5-carboxamide (12b)
10) 2-Imino-3-mesityl-4-methyl-N-phenyl-2,3-dihydrothiazole-5-carboxamide(12c)
11) Ethyl 3-benzyl-2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylate (13)
The biological evaluation was accomplished through anti-bacterial screening for whole cell growth inhibition against gram negative Acinetobacter baumannii (ATCC-19606), also the active compounds were screened for cytotoxicity assay against human embryonic kidney cells (HEK293), and haemolysis assay against human red blood cells. The anti-bacterial screening for the synthesized compounds was performed by CO-ADD (the community for anti-microbial drug discovery), which funded by the Wellcome Trust (UK) and The University of Queensland (Australia).
Initial biological screening of the tested compounds showed anti-bacterial activity of the tested compounds 8a, 8b and 11 against Acinetobacter baumannii (ATCC-19606), with MIC value = 32 μg/mL. Further microbiological investigations, compounds 8a, 8b and 11 showed anti-bacterial activity against Acinetobacter baumannii (ATCC-19606) with MIC values = 4-0.25 μg/mL. Interestingly, compound 11 showed the highest potency with MIC value ≤ 0.25 μg/mL which significantly higher than the lead compound 2-(4-chlorophenyl)-5,5-dimethyl-1,2,4-triazolidine-3-thione (MIC value = 2 μg/mL).
The tested compounds exhibited safety profile against human embryonic kidney (HEK-293) cells and human red blood cells.