Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents

Abstract

In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38 cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98 µg/ml) and antifungal (MIC: 0.49-0.98 µg/ml) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81 µg/mL, 2 respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.

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“…The methoxy, ethoxy, and alkyl groups were found to be favorable for the activity. Compounds (18) (MIC = 0.39 μg/mL) were more and equally potent compared to standard drug isoniazid, (MIC = 0.78 μg/mL) 78 .…”

“…SAR (structural activity relationship) study concluded that chloro and methyl substitution are favorable for the activity. Compound (2) (MIC < 0.98 μg/mL) was established to be nearly all active with equal potency both as antifungal and as antimicrobial relative to ciprofloxacin (MIC < 3.90 μg/mL) and amphotericin B (MIC < 1.95 μg/mL), respectively 55 . Recently, synthesized and evaluated various indole derivatives containing heterocyclic nucleus were explored as antimicrobial agents.…”

“…All the synthesized compounds were screened through invitro study against L. donovani. Pharmacophore model was also developed for diindolyl methane derivatives (55) showed excellent statistical parameters.…”

Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors

“…sulfonamides and their bioisosteres, carboxylates and their derivatives, phenols, and so on). Thiazolidinones were recently assayed as potent antifungal agents [39,40], and some of them were tested as carbonic anhydrase inhibitors in order to discover and develop innovative mechanisms of inhibition [37,41]. From the data reported in Table 2, it is possible to extrapolate a very remarkable selectivity profile of our thiazolidinones against this fungal β-CA over the two ubiquitous human isoforms (hCA I and II) being the selectivity index (SI) for compound 4h > 1000 (expressed as the ratio between K I CA I or II and K I CgNce103 values) and >100 for most of the other compounds.…”

Design and Synthesis of Novel 1-((Dimethylamino)methyl)-3-(4-(3-(Substitute Dphenyl)-4-Oxothiazolidin-2-Yl)phenylimino)-5-Nitroindolin-2-Ones as Potent Antitubercular Agents

“…Isatins have emerged as antimicrobial agents due to their broad spectrum of in vitro and in vivo antimicrobial activities [19][20][21][22][23][24][25][26][27]. In addition, thiazolidinone also reported to possess various biological activities particularly antimicrobial activity [28][29][30][31][32]. Due to the importance, we planned to synthesize compounds with isatin functionality coupled with thiazolidinone as possible antitubercular and antimicrobial agents which could furnish better therapeutic results.…”