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A series of indole-based spirothiazolidinones have been designed, synthesized and evaluated, in vitro, for their antitubercular, antiviral, antibacterial, and antifungal activities. The structures of the new compounds were established by IR, 1 H NMR, 13 C NMR (proton decoupled, APT, and DEPT), electrospray ionization mass spectrometry, and microanalysis. Compounds bearing a phenyl substituent at position 8 of the spiro ring, exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at concentrations of 3.9 and 7.8 µM. Still, some of the tested compounds displayed activity on mycobacteria with MIC values of 16 and 31 µM. Four of the indole-spirothiazolidinone derivatives were found to be moderately active against Punta Toro virus, yellow fever virus or Sindbis virus in Vero cells. The antiviral EC 50 values were in the range of 1.9-12 µM and the selectivity index (ratio of cytotoxic to antivirally effective concentration) was above 10 in some cases. The most potent effect was seen with the compound that is methylated at positions 2 and 8 of the spirothiazolidinone system. Graphic abstract

In our pursuit of developing the novel, potent, and selective antimicrobial agents, we managed to obtain the quinolinequinone for their antimicrobial profile with minimal inhibitory concentrations (MICs) determined against a panel of seven bacterial strains (three gram-positive and four gram-negative bacteria) and three fungi. The structureactivity relationship (SAR) for the quinolinequinone class of antimicrobials was determined. Interestingly, QQ1, QQ4, QQ6-9, QQ12, and QQ13 displayed equal antibacterial potential against S. aureus (MIC = 1.22 mg/L), respectively, to the standard positive control Cefuroxime-Na. QQ10 had the best inhibitory activity with the MIC value of 1.22 mg/L (fourfold more potent compared to reference standard Clotrimazole) against Candida albicans. On the other hand, while QQ10 is not too effective against gram-positive bacteria as much as the other analogs, QQ10 was the most effective quinolinequinones against fungi. Selected quinolinequinones were further evaluated for the mode of action, using in vitro antibiofilm activity, bactericidal activity by using time-kill curve assay, antibiofilm activity, and potential antimicrobial activity against each of 32 clinically obtained resistant strains of Gram-positive Bacteria. The results also revealed that the QQ14 had specific antifungal activity against fungi in particular C. albicans. Our results clearly showed that quinolinequinones are much more active in the inhibition of the biofilm attachment process than the inhibition of mature biofilm formation. Thus, as treatment options are narrowing for Methicillin-resistant Staphylococcus spp., Vancomycin-resistant Staphylococcus spp. daily, the quinolinequinones reported herein display promise as the lead candidates for further clinical applications against serious infections.

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Objectives: The ceragenins, or CSAs, were designed to mimic the activities of antimicrobial peptides and represent a new class of antimicrobial agent. The aim of this study was to comparatively investigate the antimicrobial activities of first/second generation ceragenins and various antibiotics against multidrug-resistant (MDR) Klebsiella pneumoniae, including colistin-resistant bacteria. Also, the synergistic effects of two ceragenins with colistin or meropenem were investigated with six K. pneumoniae strains presenting different resistant patterns. Methods: Minimal inhibition concentrations (MICs) were determined by the microdilution method according to the CLSI. Antibiotic combination studies were evaluated by the time–kill curve method. Results: MIC50 and MIC90 values of tested ceragenins ranged from 8 to 32 mg/L and 16 to 128 mg/L. Overall, among the ceragenins tested, CSA-131 showed the lowest MIC50 and MIC90 values against all microorganisms. The MICs of the ceragenins were similar or better than tested antibiotics, except for colistin. Synergistic activities of CSA-131 in combination with colistin was found for strains both at 1× MIC and 4× MIC. No antagonism was observed with any combination. Conclusions: First-generation ceragenins CSA-13 and CSA-44 and second-generation ceragenins CSA-131, CSA-138 and CSA-142 have significant antimicrobial effects on MDR K. pneumoniae. Mechanisms allowing resistance to clinical comparator antibiotics like colistin did not impact the activity of ceragenins. These results suggest that ceragenins may play a role in treating infections that are resistant to known antibiotics.