New acrylamide-sulfisoxazole conjugates as dihydropteroate synthase inhibitors. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Nasr, Tamer; Bondock, Samir; Ibrahim, Tamer M.; Fayad, Walid; Ibrahim, Ahmed B.; AbdelAziz, Neveen A.; Sakr, Tamer M.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: Antimicrobial agents -- Molecular docking -- Radiolabeling -- Sulfisoxazole -- Acrylamide -- Thioglycoside; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115444
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: New functionalized acrylamide derivatives bearing sulfisoxazole moiety were synthesized and evaluated for their in vitro antimicrobial activities. In vivo pharmacokinetic study was carried out. Molecular modeling studies indicated that these compounds were able to inhibit the microbial dihydropteroate synthase enzyme (DHPS). Highlights: Acrylamide derivatives bearing sulfisoxazole moiety were synthesized. Target compounds were evaluated in vitro as antimicrobial agents. DHPS is confirmed to be a putative target for these compounds. Docking experiments against DHPS rationalized the observed activities. 99m Tc-5g complex could be used as a diagnostic radio imaging material. Abstract: New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E -configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli . Interestingly, compounds 5f-g, 7c, 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor ( p -aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99m Tc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice.