Sat, 16 Dec 2017

Design and Synthesis of Pyridine-amide Based Compounds Appended Naproxen Moiety as Anti-Microbial and Anti-Inflammatory Agents

Yousry A. Ammar,1 Eman A. Fayed,2 Ashraf H. Bayoumi,3  Marwa A. Saleh2, Moustafa E. El-Araby,4,5*

1. Organic Chemistry Department, Faculty of Science (boys), Al-Azhar University, Nasr City, Cairo, Egypt.

2. Organic chemistry Department, Faculty of Pharmacy, Al-Azhar University (Girls),

3. Organic Chemistry Department, Faculty of Pharmacy (boys), Al-Azhar University.

4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi Arabia.

5. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt.


ABSTRACT

A series of pyridinamide-containing naproxen derivatives were synthesized through different routes starting with naproxenoyl chloride (2) which, upon reaction with 2-or 3-aminopyridine, gave the corresponding naproxenamide derivatives 3a,b. Also, urea derivatives 5a,b were obtained through the reaction of compound 2 with sodium azide followed by reaction with 2-or 3-aminopyridene via Curtius rearrangement. In addition, naproxenoyl isothiocyanate was synthesized and reacted with 2- or 3-aminopyridine, where the thiourea derivatives 7a,b were obtained. Furthermore, cyanoacetanilide 9 was synthesized and reacted with acetylacetone, arylidenemalononitriles or arylidenecyanoacetate to furnish the corresponding pyridine amide derivatives 10-13. All compounds were screened for anti-inflammatory activity using an in vivo rat paw edema model, from which six of them exhibited higher potency than naproxen. The ulcerogenic effect of most of the active compounds was also screened. In ulcerogenicity screening, the potent anti-inflammatory compounds 3b, 5a and 5b were devoid of any ulcerative effect. This is contrary to naproxen which caused 100% ulcerative effect on all tested animals. Structure-based molecular modeling described that the virtual screening agrees with the SAR of in vivo anti-inflammatory and ulcerogenic activities. Furthermore, all the synthesized compounds were screened for their anti-microbial activity.

Keywords: Naproxen, Pyridine, Anti-inflammatory, Ulcerogenic, Antimicrobial activities, Surflex, Docking, COX-2, SYBYL-X


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