A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses.
Using ciprofloxacin as a reference, compounds 1–21 were screened in vitro against Gram-positive
bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such
as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had
antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2–6, oxadiazole
derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against
Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested
had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans,
ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole).
The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against
E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50
values (1.47, 6.80, and 8.92 M, respectively) against E. coli topo IV in comparison to novobiocin
(IC50 = 11 M).

DNA gyrase and topoisomerase IV (topo IV) inhibitors are among the most interesting antibacterial drug classes
without antibacterial pipeline representative. Twenty-four new quinoline-1,3,4-oxadiazole and quinoline-1,2,4-
triazole hybrids were developed and tested against DNA gyrase and topoisomerase IV from Escherichia coli and
Staphylococcus aureus. The most potent compounds 4c, 4e, 4f, and 5e displayed an IC50 of 34, 26, 32, and 90 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). The activities of 4c, 4e, 4f, and 5e on DNA gyrase from S. aureus were weaker than those on E. coli gyrase. Compound 4e showed IC50 values (0.47 μM and 0.92 μM) against E. coli topo IV and S. aureus topo IV, respectively in comparison to novobiocin (IC50 = 11, 27 μM, respectively). Antibacterial activity against Gram-positive and Gram-negative bacterial strains has been studied. Some compounds have demonstrated superior antibacterial activity to ciprofloxacin against some of the bacterial strain studied. The most active compounds in this study showed no cytotoxic effect with cell
viability>86%. Finally, a molecular docking analysis was performed to investigate the binding mode and interactions of the most active compounds to the active site of DNA gyrase and topoisomerase IV (topo IV)
enzymes.

A new series of pyrimidine-5-carbonitrile derivatives 8a-p carrying the 1,3-thiazole moiety has been designed
and synthesized as novel anti-inflammatory EGFR inhibitors with cardiac and gastric safety profiles. 8a-p have
been assessed for their inhibitory activity against COX-1/COX-2 activity. Compounds 8h, 8n, and 8p were found
to be potent and selective COX-2 inhibitors (IC50 = 1.03–1.71 μM) relative to celecoxib (IC50 = 0.88 μM). The
most potent COX-2 inhibitors have been further investigated for their in-vivo anti-inflammatory effect. Compounds
8h, 8n, and 8p showed anti-inflammatory activity up to 90%, 94% and 86% of meloxicam after 4 h
interval. 8h, 8n, and 8p showed higher gastric safety profiles than meloxicam. A substantial reduction in serum
concentrations of PGE2, TNF-α, IL-6, iNO and MDA and a significant induction of TAC was also observed. In vivo
experiments on heart rate and blood pressure established the cardiovascular safety profile of 8h, 8n, and 8p.
Anti-proliferative and wild-type EGFR inhibitory assays displayed similar results to selective COX-2 inhibition
where compounds 8h, 8n, and 8p had a superior inhibition than other tested ones. Molecular docking study
demonstrated that these compounds revealed similar orientation and binding interactions as selective COX-2
inhibitors with a higher liability to enter the side pocket selectively. Also, they interacted with EGFR tyrosine
kinase main amino acids similar to erlotinib with a strong binding energy score.

FAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of
targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in
which the kinase has been implicated in promoting metastases. Consequently, designing and developing
potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as
a promising tool in our armamentarium for treating diverse cancers. This review comprehensively
summarizes the different classes of synthetically derived compounds that have been reported as potent
FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed
to slow down the emergence of drug resistance is discussed.

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and
focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of
both HDAC2 (IC50 ¼ 0.09e1.40 mM) and FAK (IC50 ¼ 12.59e36.11 nM); 6a revealed the highest activity
with IC50 values of 0.09 mM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to
reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and
Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M
phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is
observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK
inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized
by molecular docking. Taken together, these findings highlight the potential of 6a as a promising
dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.