New Inducible Nitric Oxide Synthase and Cyclooxygenase-2 Inhibitors, Nalidixic Acid Linked to Isatin Schiff Bases via Certain l-Amino Acid Bridges.
A series of new Schiff bases were synthesized by condensation of isatins with the nalidixic acid-l-amino acid hydrazides. Prior to hydrazide formation, a peptide linkage has been prepared via coupling of nalidixic acid with appropriate l-amino acid methyl esters to yield 3a-c. The chemical structures of the new Schiff bases (5b and 5d-h) were confirmed by means of IR, NMR, mass spectroscopic, and elemental analyses. The anti-inflammatory activity of these Schiff bases was evaluated via measurement of the expressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells model. The Schiff bases exhibited significant dual inhibitory effect against the induction of the pro-inflammatory iNOS and COX-2 proteins with variable potencies. However, they strongly down-regulated the iNOS expression to the level of 16.5% ± 7.4%-42.2% ± 19.6% compared to the effect on COX-2 expression (<56.4% ± 3.1% inhibition) at the same concentration (10 μM). The higher iNOS inhibition activity of the tested Schiff bases, relative to that of COX-2, seems to be a reflection of the combined suppressive effects exerted by their nalidixic acid, isatins (4a-c), and l-amino acid moieties against iNOS expression. These synthesized nalidixic acid-l-amino acid-isatin conjugates can be regarded as a novel class of anti-inflammatory antibacterial agents.
Department of Pharmaceutical Chemistry, Drug Exploration &amp; Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. anaglah@ksu.edu.sa.|Peptide Chemistry Department, National Research Centre, 12622-Dokki, Cairo 12311, Egypt. anaglah@ksu.edu.sa.
Ahmed M
AM
Naglah
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. afahmed@ksu.edu.sa.|Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. afahmed@ksu.edu.sa.
Atallah F
AF
Ahmed
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan. wzh@mail.nsysu.edu.tw.
Zhi-Hong
ZH
Wen
Department of Pharmaceutical Chemistry, Drug Exploration &amp; Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. omarfatata22@gmail.com.
Mohamed A
MA
Al-Omar
Department of Pharmaceutical Chemistry, Drug Exploration &amp; Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. afali2412@gmail.com.|Applied Organic Chemistry Department, National Research Centre, 12622-Dokki, Cairo 12311, Egypt. afali2412@gmail.com.
Abd El-Galil E
Ael-G
Amr
Peptide Chemistry Department, National Research Centre, 12622-Dokki, Cairo 12311, Egypt. cm_atahmed@yahoo.com.
Atef
A
Kalmouch
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics; D007510:Isatin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D009268:Nalidixic Acid / Q000138:chemical synthesis / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000067996:RAW 264.7 Cells; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D012545:Schiff Bases; D009268:Nalidixic Acid; D007510:Isatin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2
">l-amino acid; COX-2; Schiff base; anti-inflammatory; iNOS; isatin; microwave irradiation; nalidixic acid