Synthesis and Biological Evaluation of New Pyridothienopyrimidine Derivatives as Antibacterial Agents and Escherichia coli Topoisomerase II Inhibitors

Abstract

The growing resistance of bacteria to many antibiotics that have been in use for several decades has generated the need to discover new antibacterial agents with structural features qualifying them to overcome the resistance mechanisms. Thus, novel pyridothienopyrimidine derivatives (2a,b–a,b) were synthesized by a series of various reactions, starting with 3-aminothieno[2,3-b]pyridine-2-carboxamides (1a,b). Condensation of compounds 1a,b with cyclohexanone gave 1’H-spiro[cyclohexane-1,2’-pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidin]-4’(3’H)-ones (2a,b), which in turn were utilized to afford the target 4-substituted derivatives (3a,b–8a,b). In vitro antibacterial activity evaluations of all the new compounds (2a,b–8a,b) were performed against six strains of Gram-negative and Gram-positive bacteria. The target compounds showed significant antibacterial activity, especially against Gram-negative strains. Moreover, the compounds (2a,b; 3a,b; 4a,b; and 5a,b) that exhibited potent activity against Escherichia coli were selected to screen their inhibitory activity against Escherichia coli topoisomerase II (DNA gyrase and topoisomerase IV) enzymes. Compounds 4a and 4b showed potent dual inhibition of the two enzymes with IC50 values of 3.44 µΜ and 5.77 µΜ against DNA gyrase and 14.46 µΜ and 14.89 µΜ against topoisomerase IV, respectively. In addition, docking studies were carried out to give insight into the binding mode of the tested compounds within the E. coli DNA gyrase B active site compared with novobiocin.

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

“…Moreover, two-fold serial dilution approach was used to find out the Minimum Inhibitory Concentration (MIC) values (expressed in μg mL −1 ) for the examined compounds. 68,69 The obtained data were recorded in ( Table 4 ).…”

Synthesis, Molecular Docking, and Biofilm Formation Inhibitory Activity of Bis(Indolyl)Pyridines Analogues of the Marine Alkaloid Nortopsentin

“…Therefore, we need to choose three of the most important antimicrobial target enzymes to study the ability of our compounds to inhibit them using molecular docking technique; the best methods to expect the inhibitory activity theoretically. In addition, the presence of the pyridine ring encourages us to study the tree enzymes, since pyridine has a broad spectrum of biological activity and is a good inhibitor for Gyrase B and topoisomerase [ 34 ].…”

Pyridine Compounds with Antimicrobial and Antiviral Activities

“…El-Deen et al [ 82 ] reported the synthesis of the pyridothienopyrimidine derivatives 196 – 198 in good yields (70–81%) from compounds 195a – 195b , as can be seen in Scheme 42 . The in vitro evaluation of these compounds against six strains of both Gram-positive ( S. aureus , B. Subtilis , B. cereus ) and Gram-negative ( E. coli , S. typhimurium , P. aeruginosa ) bacteria compared with Amoxicillin trihydrate as a reference drug showed a significant antibacterial activity for all compounds, especially against Gram-negative strains, with MIC values ranging from 7.81 to 62.5 μg mL −1…”