DNA gyrase is a promising target for antibacterial agents. Several classes of small molecule inhibitors have been discovered in recent decades, but none of these have reached the market. We have designed a small library of 1,2,4-oxadiazole/pyrrolidine hybrids with mid nanomolar inhibitory and potent antibacterial activities against DNA gyrase and topoisomerase IV. Compounds 9, 15, 16, 19, and 21 inhibited Escherichia coli DNA gyrase to a similar extent as the reference compound, novobiocin, with inhibitory values ranging from 120 nM to 270 nM. Compound 16 was one of the most potent compounds in the series, with an IC50 value of 120 nM against E. coli
gyrase, which is lower than the IC50 value of novobiocin (170 nM). Compound 16 had the highest inhibitory activity, with minimum inhibitory concentrations (MIC) of 24 and 62 ng/mL against Staphylococcus aureus and E. coli, respectively, which compared favorably with ciprofloxacin (30 and 60 ng/mL, respectively). Compounds 9, 15, 19, and 21 were similar to novobiocin in terms of their activity against E. coli and S. aureus topoisomerase IV, while compound 16 was more potent than novobiocin.

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into
reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-
Sharpless reaction) was developed to tether 3,3’-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-
hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed
attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products
are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one,
achieving IC50 = 1.2  0.2 M and 1.4  0.2 M against MCF-7 and Panc-1 cell lines, respectively.
Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M
phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant
pro-apoptotic activity is indicated by annexin V-FITC staining.

A novel series of tri-aryl imidazole derivatives 5a–n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3–1.3 M, and selectivity ratio for hCA IX over hCA XII = 5–12) relative to acetazolamide (Ki = 0.03 mM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than
other tested compounds (with GI50 = 2.3 and 2.8 mM, respectively) in comparison to doxorubicin (GI50 = 1.1 mM). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The
synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The
structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13,
14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-
E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2
compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 μM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal
property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 μM
concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is
primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2
Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with
an IC50 of 2.58 μM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of
the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years
after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19–31 was synthesized as
selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target
compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82–1.12 μM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual
COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more
potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds
were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against
cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-
2/sEH active sites to explain their binding modes.

New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been
designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results
showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17–19 showed superior antiproliferative
activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed
promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19
increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19
demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of
EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.

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.