Synthesis and Antibacterial Evaluation of a New Series of N-Alkyl-2-alkynyl/(E)-alkenyl-4-(1H)-quinolones

Abstract

To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some N-alkyl-4-(1H)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for in vitro antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain Mycobacterium bovis BCG, and methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase of Mycobacterium tuberculosis. The lowest MIC value of 0.5 mg/L (1.2–1.5 µM) was found against M. fortuitum and M. smegmatis. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 µM concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2–128 mg/L (5.3–364.7 µM), and M. bovis BCG with an MIC value of 25 mg/L (66.0–77.4 µM). In addition, the compounds inhibited the MurE ligase of M. tuberculosis with moderate to weak activity showing IC50 values of 200–774 µM. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of N-alkyl-2-(E)-alkenyl-4-(1H)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity.

1,2-Substituted 4-(1H)-Quinolones: Synthesis, Antimalarial and Antitrypanosomal Activities in Vitro

“…The isatoic anhydride derivatives bearing ethyl, n -propyl, n -butyl, allyl, propargyl and 2-bromoethyl, which served as important intermediates for the synthesis of our 4-(1 H )-quinolone derivatives were prepared by treatment of the commercially available isatoic anhydride with the corresponding halolalkanes, allyl bromide, propargyl bromide and 1,2-dibromoethane by a previously described method [15].…”

“…Purification of the compounds was carried out using CC eluting with cyclohexane/ethyl acetate. The spectral data of compounds 18a – g , 19 , 28 – 30 , 35 , 36a – b were reported in our previous work [14,15,22].…”

Recent Developments in the Synthetic Strategies of 4‐Quinolones and Its Derivatives

“…They are considered bioisosteres of the chromen-4-one scaffold and exist in equilibrium with its tautomeric form i. e. 4-hydroxyquinoline (figure 1). [1] They are known to possess a broad range of biological activities which includes antimicrobial, [2,3] antiviral, [4][5] antiplasmodial, [6] antioxidant, [7] anti-inflammatory, [8] anticholinesterase, [9] anticonvulsant, [10] anticancer, [11] neuroprotective, [12] genitourinary infections, [13] prostatitis, respiratory diseases, as well as skin and soft tissue infections. [14][15] In addition to the above, now they are widely explored as anti-HIV, [16] antimalarial agents, [17,18] alkaline phosphatase inhibitors, [19] antifilarial agents, [20] and antidiabetic agent, [21] for the development of novel therapeutic agents.…”

Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis

“…While the Mur pathway in other pathogens has been exploited in the past for developing inhibitors 25 26 27 28 29 , fewer such studies 30 31 32 33 have been carried out on the Mur enzymes from Mtb where inhibitors have been screened using a single Mur enzyme as the target (leading to identification of inhibitors for only one enzyme at a time). This method not only makes the screening of inhibitors time consuming, laborious and expensive, but also has an inherent potential for finding drugs against which the pathogen could develop resistance in a rather short time.…”