Synthesis, Docking Studies, and In Vitro Evaluation of Some Novel Thienopyridines and Fused Thienopyridine–Quinolines as Antibacterial Agents and DNA Gyrase Inhibitors

Abstract

A series of novel thienopyridines and pyridothienoquinolines (3a,b–14) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles 1a and 1b. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds 3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b, and 14 showed significant growth inhibition activity against both Gram-positive and Gram-negative bacteria compared with the reference drug. The most active compounds (4a, 7a, 9b, and 12b) against Staphylococcus aureus were also tested for their in vitro inhibitory action on methicillin-resistant Staphylococcus aureus (MRSA). The tested compounds showed promising inhibition activity, with the performance of 12b being equal to gentamicin and that of 7a exceeding it. Moreover, the most promising compounds were also screened for their Escherichia coli DNA gyrase inhibitory activity, compared with novobiocin as a reference DNA gyrase inhibitor. The results revealed that compounds (3a, 3b, 4a, 9b, and 12b) had the highest inhibitory capacity, with IC50 values of 2.26–5.87 µM (that of novobiocin is equal to 4.17 µM). Docking studies were performed to identify the mode of binding of the tested compounds to the active site of E. coli DNA gyrase B.

Synthesis, Antimicrobial Activity and Molecular Docking of Novel Thiourea Derivatives Tagged with Thiadiazole, Imidazole and Triazine Moieties as Potential DNA Gyrase and Topoisomerase IV Inhibitors

“…Prompted by the kinase inhibitory results, compound 8 was selected for molecular docking against E. coli DNA gyrase B and Topoisomerase IV using MOE (Molecular Operating Environment) software 10.2008 [30]. The protein data bank files (PDB: 1AJ6 and 1S14) [26,31] was downloaded and the docking simulation was verified firstly by redocking of the native ligand (novobiocin) in the binding pockets of E. coli DNA gyrase B and Topoisomerase IV with energy score (S) = −10.77 and −7.88 kcal/mol and root mean standard deviation (RMSD) = 0.86 and 0.79 Å, respectively.…”

“…As reported previously in docking of novobiocin [26,31], fixation within the active site of DNA gyrase B kinase was done through two hydrogen bonds with the essential amino acids Asp46 and Asp73 and arene-cation interaction with Arg76. While within the ATP binding pocket of Topoisomerase IV, it linked to the four key amino acids Asn1042, Asp1069, Asp1077 and Arg1132 via hydrogen bonding (Figure 3).…”

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

“…As reported in docking of novobiocin, having a coumarin core linked to oxan-4-yl moiety, the protons of the hydroxyl group of oxan-4-yl and NH 2 of the carbamate group formed hydrogen bonds within the active site of DNA gyrase B kinase via the backbone of Asp46 and the side chain of Asp73 . Furthermore, the coumarin scaffold shared fixation through an arene–cation interaction with the essential amino acid Arg76 [ 37 , 47 ].…”

“…At the beginning, the co-crystallized ligand was re-docked into the assigned active E. coli DNA gyrase B enzyme to evaluate the root mean square deviation value. Then, the molecular docking procedure was performed for the newly synthesized compounds ( 2a , b ; 3a , b ; 4a , b ; 5a , b ) into the ATP-binding site of E. coli DNA gyrase B (PDB code: 1AJ6 and 1S14), following the reported method [ 37 ].…”

“…As a result, thieno[2,3- b ]pyridine compounds and their fused derivatives with the bioactive pyrimidine ring [ 28 , 29 ] have attracted great interest in the last decade; several pyrido[3’,2’:4,5]thieno[3,2- d ]pyrimidine derivatives were synthesized and gave significant pharmacological properties as antimicrobial [ 30 , 31 , 32 ], anticancer [ 33 , 34 ] and protein kinase inhibitors [ 35 , 36 ]. Moreover, some thieno[2,3- b ]pyridine derivatives [ 37 ] and pyrimidine-based compounds [ 38 , 39 ] have been discovered in recent years as potent DNA gyrase and/or topoisomerase IV inhibitors, which encourage the design and synthesis of novel thienopyridine-fused pyrimidine compounds to obtain enhanced antibacterial activity ( Figure 1 ).…”