A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3
(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of
60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity
against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney.
Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor
subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI50 level. In vitro assaying revealed
tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study
revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds
exhibited high binding affinities (ΔGb = - 12.49 to -12.99 kcal/mol) toward tubulin compared to CA-4 (- 8.87
kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they
interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations
suggest that tubulin is a possible target for these compounds.

A series of novel piperine–resveratrol hybrids 5a–h was designed, synthesized, and structurally elucidated
by IR, and 1H, 13C, and 19F NMR. Antiproliferative activities of 5a–h were evaluated by NCI against sixty
cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed
a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth
inhibition percentage of
0.49 and
2.83, respectively. In addition, 5b recorded significant activity
against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a–h
hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their
antiproliferative action. Results showed that compounds 5a–h were more potent inhibitors of Sirt-2 than
Sirt-1 at 5 mm and 50 mm. Compound 5b showed the strongest inhibition of Sirt-2 (78  3% and 26  3%
inhibition at 50 mM and 5 mM, respectively). Investigation of intermolecular interaction via Hirschfeld
surface analysis indicates that these close contacts are mainly ascribed to the O–H/O hydrogen
bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b
was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with
the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of
the NAD+ C-pocket. Collectively, these findings would contribute significantly to better understanding
the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2
inhibitors.

A novel series of 19 quinoline/1,2,4-triazole hybrid 6a-i and 7a-j was synthesized and evaluated in vitro as dual COX-2/5-LOX inhibitors. Compounds 6e, 6i , and 7e displayed the highest potency and selectivity for inhibiting COX-2 activity (IC 50 = 7.25, 8.13, and 8.48 nM, respectively; selectivity index (COX-1/COX- 2) = 44.89, 30.30, and 33.47, respectively) in comparison to celecoxib (COX-2 IC 50 = 42.60 nM; selectivity index (SI) = 8.05). The anti-inflammatory activity of the newly synthesized compounds was further examined in vivo using a carrageenan induced paw edema assay. Interestingly, the in vitro findings of the COX inhibitory assay were consistent with the in vivo assay. Moreover, 6e, 6i , and 7e showed a substantial reduction in serum concentrations of PGE 2 , TNF- α, IL-6. Molecular docking analysis of compounds 6e , 6 f, 6i, 7e , and 7f revealed high binding affinities toward COX-2 compared to COX-1, which was matched with the experimental results. In addition, these compounds exhibited different binding orientations into the active site of COX-2, which were dependent on the type of substitutions on N4 of the triazole ring. Among the tested derivatives, compounds 6e, 6i and 7e which showed high selectivity to COX-2, exhibited hydrogen bonding interactions with key amino acids in COX-2 such as Arg120, Arg513, and/or Glu524. In addition, the tested compounds also showed multiple hydrogen bonds with the Arg101, Val110, Arg138 or His130 in 5-LOX. These findings show, taken together, that those derivatives are good leads to potential anti-inflammatory agents with lowest gastric damage.

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.