Design, Synthesis and Pharmacological Evaluation of Some C₃ Heterocyclic-Substituted Ciprofloxacin Derivatives as Chimeric Antitubercular Agents

Abstract

A series of new C 3 heterocyclic-substituted ciprofloxacin derivatives were prepared from ciprofloxacin acid hydrazide as possible chimeric molecules. They were evaluated for their possible in vitro antibacterial (agar cup/bore diffusion method) and antitubercular (Lowenstein-Jensen (LJ) slant method) activities. The results indicated that all the test compounds are highly effective against all the bacterial strains and have shown excellent anti-tubercular activity against normal, multidrug resistant and extensively drug resistant strains of Mycobacterium tuberculosis. They were found to be more potent antibacterial and antitubercular agents than the standard, ciprofloxacin. The minimum inhibitory concentration (MIC)'s of all the compounds against M. tuberculosis were found to be 0.0625 µg/mL as compared to ciprofloxacin (MIC 2 to > 8 µg/mL). Molecular docking studies were performed by using AUTODOCK 4.2 on the new ciprofloxacin derivatives at the active site of crystal structure of fluoroquinolones target enzyme Mtb DNA gyrase GyrA N-terminal domain (PDB ID: 3ILW) and also on the active site of crystal structure of chosen heterocyclics target enzyme enoyl-acyl carrier protein (ACP) reductase enzyme (PDB ID: 4TZK). Interestingly, almost all the compounds have shown relatively greater binding affinity at both the active sites than ciprofloxacin. Compound 6 exhibited the highest affinity for 3ILW and 4TZK.

Discovery of Novel Inhibitors of Bacterial DNA Gyrase Using a QSAR-Based Approach

“…The structures of ciprofloxacin templates and predefined substitution sites R 1 , R 2 , and R 3 are shown in Figure . The substitution for R1 was considered keeping in mind that aromatic amines or bulky groups are favorable, , whereas smaller group substitution was done at R2 and R3 positions. − Using the virtual combinatorial library tool by cheminfo.org, 29828 analogues were designed to create the virtual library, and after ADMET profiling using the swissADME tool, 2550 analogues were sorted out for further screening (Table ). These compounds were further filtered through the NN-classification-based QSAR model; 675 analogues were predicted to show inhibitory activity against the DNA gyrase A subunit.…”

A Comprehensive Review on Chemical Synthesis and Chemotherapeutic Potential of 3-Heteroaryl Fluoroquinolone Hybrids

“…Thus, ref. [ 32 ] evidenced the synthesis and evaluation of antibacterial activity of ciprofloxacin C3 hybrids with isatins, phthalimides and oxadiazoles. In vitro antibacterial evaluation was made using disk diffusion and serial dilution methods, and antitubercular activity was measured using the Lowenstein–Jensen (LJ) method.…”

“…They can be introduced into C-3 via the formation of different functional derivatives of carboxylic acids that are presented in Scheme 1 . For instance, alkylation offers an opportunity to further obtain hydrazine derivatives [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. The carboxylic group can be easily turned into an amide group with the subsequent formation of nitriles [ 56 ].…”

“…As for further cyclization, literature data present investigations that describe synthesized 3-heteroaryl hybrids of fluoroquinolones with oxadiazole [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 57 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], isoxadiazole [ 55 , 68 ], triazole [ 25 , 26 , 30 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 65 , 71 , 72 , 73 , 74 , 75 ], thiadiazole [ 25 , 26 , 47 , 59 , 60 , 71 , 75 , 76 , 77 ,…”

“…One of the leading positions among them is given to the oxadiazole ring that was used for modification of fluoroquinolones of the second (norfloxacin, ciprofloxacin, ofloxacin, pefloxacin) and third (levofloxacin, enrofloxacin) generations [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 57 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. The main routes for the introduction of the oxadiazole ring into C-3 of fluoroquinolones are depicted in Scheme 2 .…”