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Antibiotics 2014, 3(3), 244-269; doi:10.3390/antibiotics3030244
Article

Synthesis, Antibacterial Evaluation and QSAR of α-Substituted-N4-Acetamides of Ciprofloxacin and Norfloxacin

1,2,* , 1
, 3
, 4
, 1
, 2,5
 and 2,5
1 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box (3030), Irbid 22110, Jordan 2 College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia 3 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan 4 Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box (3030), Irbid 22110, Jordan 5 King Abdulaziz Medical City, National Guard Health Affairs, Riyadh 11426, Saudi Arabia
* Author to whom correspondence should be addressed.
Received: 4 April 2014 / Revised: 19 May 2014 / Accepted: 29 May 2014 / Published: 25 June 2014
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Abstract

Twenty six α-substituted N4-acetamide derivatives of ciprofloxacin (CIPRO) and norfloxacin (NOR) were synthesized and assayed for antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Bacillus subtilis. The derivatives were primarily more active against Gram-positive bacteria. The CIPRO derivatives, CD-7 (Ar = 3-chlorophenyl), CD-9 (Ar = 2-pyrimidyl) and CD-10 (α-phenyl, Ar = 2-pyrimidyl), exhibited lower MIC values, 0.4–0.9 μM, against Staphylococcus aureus than CIPRO, while only compound CD-10 exhibited better activity, 0.1 μM, against Bacillus subtilis than CIPRO. In addition, compounds CD-5 (Ar = 2-methoxyphenyl), CD-6 (α-phenyl, Ar = 2-methoxyphenyl), CD-7 (Ar = 3-Chlorophenyl), CD-8 (α-phenyl, Ar = 3-chlorophenyl) and CD-9 (Ar = 2-pyrimidyl) showed MIC values below 1.0 μM against this strain. The NOR derivatives showed lower activity than NOR itself against Staphylococcus aureus, although ND-6 (α-phenyl, Ar = 2-methoxyphenyl) and ND-7 (Ar = 3-chlorophenyl) showed MIC values less than 2 μM. Two NOR derivatives, ND-7 and ND-6, exhibited MIC values of 0.7 and 0.6, respectively, which were comparable to that of NOR against Bacillus subtilis, while compounds ND-8 (α-phenyl, Ar = 3-chlorophenyl) and ND-10 (α-phenyl, Ar = 2-pyrimidyl) exhibited MIC values less than 1.0 μM against the same strain. QSAR revealed that while polarity is the major contributing factor in the potency against Staphylococcus aureus, it is balanced by lipophilicity and electron density around the acetamide group. On the other hand, electron density around the introduced acetamide group is the major determining factor in the activity against Bacillus subtilis, with a lesser and variable effect for lipophilicity.
Keywords: antibacterial activity; drug design; Gram-positive bacteria; QSAR; quinolones; synthesis antibacterial activity; drug design; Gram-positive bacteria; QSAR; quinolones; synthesis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Qandil, A.M.; Al-Zoubi, L.O.; Al-Bakri, A.G.; Amawi, H.A.; Al-Balas, Q.A.; Alkatheri, A.M.; Albekairy, A.M. Synthesis, Antibacterial Evaluation and QSAR of α-Substituted-N4-Acetamides of Ciprofloxacin and Norfloxacin. Antibiotics 2014, 3, 244-269.

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