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A series of novel 1,2,3-triazole-linked ciprofloxacin-chalcones 4a-j were synthesised as potential anticancer agents. Hybrids 4a-j exhibited remarkable anti-proliferative activity against colon cancer cells. Compounds 4a-j displayed IC50s ranged from 2.53-8.67 µM, 8.67-62.47 µM, and 4.19-24.37 µM for HCT116, HT29, and Caco-2 cells; respectively, whereas the doxorubicin, showed IC50 values of 1.22, 0.88, and 4.15 µM. Compounds 4a, 4b, 4e, 4i, and 4j were the most potent against HCT116 with IC50 values of 3.57, 4.81, 4.32, 4.87, and 2.53 µM, respectively, compared to doxorubicin (IC50 = 1.22 µM). Also, hybrids 4a, 4b, 4e, 4i, and 4j exhibited remarkable inhibitory activities against topoisomerase I, II, and tubulin polymerisation. They increased the protein expression level of γH2AX, indicating DNA damage, and arrested HCT116 in G2/M phase, possibly through the ATR/CHK1/Cdc25C pathway. Thus, the novel ciprofloxacin hybrids could be exploited as potential leads for further investigation as novel anticancer medicines to fight colorectal carcinoma.

Introduction: One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease. Objectives: Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases. Methods: The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied. Results: All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites. Conclusion: Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization. [ABSTRACT FROM AUTHOR]

This study intends to investigate the change process factors in relation to readiness for change during the healthcare reforms. It theorizes readiness for change as multidimensional and considers the cognitive, emotional, and intentional dimensions. This is crucial for creating a rich and holistic understanding of readiness for change. An exploratory sequential mixed method has been used to explore the change process factors and then test its connection with all the three dimensions of readiness for change. Data has been collected from four medical teaching institutes in Khyber Pakhtunkhwa, Pakistan in which healthcare reforms had been implemented. Fifteen in-depth semi-structured interviews were carried out with the healthcare staff followed by 390 survey questionnaires. Qualitative findings reveal process factors that are not previously known in the literature. This includes transforming and threatening organizational philosophy and pervious policies, mismatch of change and existing organizational resources and practices, and fear of creating a coercive work environment. The quantitative part of the study reveals the varying impact of identified process factors on individual cognitive, emotional, and intentional readiness for change. This study contributes to our current understanding of change process considering it as contextual, and by appreciating and embracing the multidimensional aspect of readiness for change, particularly the emotional and intentional dimensions. It also introduces additional change process factors to the current literature. [ABSTRACT FROM AUTHOR]