A class of quinazolone thiazoles was identified as new structural scaffolds for potential antibacterial conquerors to tackle dreadful resistance. Some prepared compounds exhibited favorable bacteriostatic efficiencies on tested bacteria, and the most representative 5j featuring the 4-trifluoromethylphenyl group possessed superior performances against Escherichia coli and Pseudomonas aeruginosa to norfloxacin. Further studies revealed that 5j with inappreciable hemolysis could hinder the formation of bacterial biofilms and trigger reactive oxygen species generation, which could take responsibility for emerging low resistance. Subsequent paralleled exploration discovered that 5j not only disintegrated outer and inner membranes to induce leakage of cytoplasmic contents but also broke the metabolism by suppressing dehydrogenase. Meanwhile, derivative 5j could intercalate into DNA to exert powerful antibacterial properties. Moreover, compound 5j gave synergistic effects against some Gram-negative bacteria in combination with norfloxacin. These findings indicated that this novel structural type of quinazolone thiazoles showed therapeutic foreground in struggling with Gram-negative bacterial infections.

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Apoptotic evasion by cancerous cells being one of the striking hallmarks of cancer has turned into a new arena of drug discovery. A large number of pathways reported that govern the apoptotic evasion have been reported. Fas-activated serine/threonine kinase (FASTK) is a member of Ser/Thr kinase family, and it has been implicated in the apoptotic evasion and, hence, the development of cancer. Keeping this in view, a series of novel thienopyrimidine-based chalcones have been synthesized and evaluated to modulate the FASTK mediated apoptotic evasion. Initial screening was done by enzyme inhibition assay and binding studies, which showed that out of 15 synthesized compounds, 3 thienopyrimidine-based chalcone derivatives possess considerably high binding affinity and enzyme inhibitory potential (nM range) for FASTK. Cell proliferation assessment of selected compounds was performed on HEK-293 and MCF-7 cells. For MCF-7 cells, compounds 2, 10, and 12 show IC values of 20.22 ± 1.50, 6.52 ± 0.82, and 8.20 ± 0.61 μM, respectively. Annexin-V and PI staining suggested that these molecules induce apoptosis in MCF-7 cells, arrest the cell cycle in the G0/G1 phase, and subsequently inhibit cell migration presumably by inhibiting FASTK and reactive oxygen species production. In conclusion, we have successfully designed, synthesized, and characterized thienopyrimidine-based chalcones that inhibit FASTK and induce apoptosis. These compounds may be exploited as potential anticancer agents.

Natural berberine-hybridized benzimidazoles as potential antibacterial agents were constructed to treat Staphylococcus aureus infection in the livestock industry. Bioassay showed that some new berberine-benzimidazole hybrids exhibited potent antibacterial efficacies, especially, the 2,4-dichlorobenzyl derivative 7d not only showed strong activity against S. aureus ATCC 29213 with the MIC value of 0.006 mM but also effectively eradicated bacterial biofilm and exhibited low toxicity toward mammalian cells. The drug combination experiments showed that compound 7d together with norfloxacin could enhance the antibacterial efficacy. Moreover, the 2,4-dichlorobenzyl derivative 7d did not show obvious propensity to develop bacterial resistance. Preliminary mechanism studies revealed that the active molecule 7d could damage the membrane integrity, stimulate ROS generation, and bind with DNA as well as S. aureus sortase A, thus exerting powerful antibacterial ability. In light of these facts, berberine-benzimidazole hybrid 7d showed a large potentiality as a new bactericide for treating S. aureus in the livestock industry.

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