Bioactive fluorenes. Part III: 2,7-dichloro-9H-fluorene-based thiazolidinone and azetidinone analogues as anticancer and antimicrobial against multidrug resistant strains agents

Abstract

Background: Thiazoles, thiazolidinones and azetidinones are highly ranked amongst natural and synthetic heterocyclic derivatives due to their great pharmaceutical potential. Results: New thiazolidinone and azetidinone class of bioactive agents based on 4-(2,7-dichloro-9H-fluoren-4-yl) thiazole moiety have been successfully synthesized. 4-(2,7-dichloro-9H-fluoren-4-yl)thiazol-2-amine was synthesized and allowed to react with various aryl/heteroaryl aldehydes to afford the corresponding Schiff base intermediates. The target thiazolidinone and azetidinone analogues have derived from Schiff bases by their reactions with thioglycolic acid and chloroacetyl chloride, respectively. The newly synthesized compounds were then evaluated for their antimicrobial activity against some multidrug resistant strains and examined for cytotoxic activity against normal lung fibroblast (WI-38), human lung carcinoma (A549), and human breast carcinoma (MDA-MB-231) cell lines to develop a novel class of fluorene-based bioactive agents. The mode of action and the binding interaction of the synthesized compound with the active sites of dihydrofolate reductase enzyme were well identified by fluorescence-activated cell sorting (FACS) analysis and molecular docking study. Conclusion: Some of the synthesized compounds showed remarkable activity against A-549 and MDA-MB-231 when compared to Taxol, which was used as a reference drug. 2,7-dichloro-9H-fluorene-based azetidinones are more efficient as antimicrobial and anticancer agents compared to dichloro-9H-fluorene-based thiazolidinones derivatives.

Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48

“…For comparison, we also tested novel fluorene-, anthraquinone-, and azobenzene-based compounds to determine the potential of these scaffolds for the inhibition of OXA-48. While these unique scaffolds have not been explicitly tested on β-lactamases previously, dichloro-fluorene derivatives and azobenzenes have been reported to show antibacterial activity, , and anthraquinone dyes have been found to bind early class D β-lactamases . The selected compounds broadly followed the “rule of three” for fragments with an MW of <300 Da, the number of hydrogen bond donors ≤3, the number of hydrogen bond acceptors ≤3, and a cLog P of ≤ 3 .…”

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design

“…Hussein et al [ 52 ] applied a hybrid-pharmacophore approach for the design of novel biologically active 4-thiazolidinones. Among the synthesized molecules, compound 54 ( Figure 21 ) exhibited the most potent cytotoxic activity and was found to be more effective on the WI-38 normal human lung fibroblast cell line, with an IC 50 of 92 µg/mL, but not as effective on the A549 and MDA-MB-31 cancer cells, with IC 50 values of 357 µg/mL and 505 µg/mL, respectively.…”

Approaches to Obtaining Fluorenes: An Alternate Perspective

“…Hussein et al combined the dichloro substituted fluorene derivative with different nitrogen and sulphur containing heterocyclic moieties like azetidinones, thiazole, and thiazolidinone, to develop a compound competent enough to fight against proliferative cells of the tumour and also against the microbes (Figure 7). [41] The synthetic scheme, as shown below, indicates that the first step involved in synthesizing the DHFR inhibitor compound 88, a fluorene-based heterocyclic molecule, is the formation of the chloroacetyl substituted dichloro fluorene 77 (Scheme 25). This was done by a simple direct halogenation reaction of the dichloro substituted fluorene derivative 76 in the presence of N-chlorosuccinimide in DCM.…”

“…Fluorene-derived aromatic carbonyl compounds like ketones are of high significance on account of the fact that they form the basis for the development of pharmaceutical materials, medicinal agents, and industrially important chemicals, particularly for the synthesis of lubricating as well as thermosetting plastic materials. [40][41][42][43] Moreover, fluorene-derived polymers, oligomers, and copolymers have garnered profound interest because of their unique electrical and optoelectronic properties and hence find applications in organic semiconductor devices that emit light, flat panel displays, and solar cells. [29,30,[35][36][37][38][39]44,45] As stated above, fluorene-containing molecules find widespread application in different fields of chemistry and owing to this; numerous methods are available for its synthesis.…”

“…Fluorene‐based compounds are flexible reagents that find a broad spectrum of synthetic applications. Fluorene‐derived aromatic carbonyl compounds like ketones are of high significance on account of the fact that they form the basis for the development of pharmaceutical materials, medicinal agents, and industrially important chemicals, particularly for the synthesis of lubricating as well as thermosetting plastic materials [40–43] . Moreover, fluorene‐derived polymers, oligomers, and copolymers have garnered profound interest because of their unique electrical and optoelectronic properties and hence find applications in organic semiconductor devices that emit light, flat panel displays, and solar cells [29,30,35–39,44,45] …”