A novel series of 1,2,3-triazole/chalcone hybrids 6a– n was designed and synthe-
sized using a molecular hybridization approach to develop a new cytotoxic agent
capable of targeting epidermal growth factor receptor (EGFR) and/or BRAF. The
antiproliferative effect of the novel hybrids was investigated against four cancer
cells using doxorubicin as a reference. Hybrids 6a, 6d, 6f– h, and 6n have the
highest antiproliferative activity (IC50 values 0.95–1.80 μM) compared to doxoru-
bicin (IC50 1.14 μM). The most potent antiproliferative derivative, compound 6d,
was also the most potent EGFR inhibitor with an IC50 of 0.09 ± 0.05 μM, which
is comparable to the reference Erlotinib (IC 50 = 0.05 ± 0.03 μM). 6d has modest
BRAF inhibitory action with an IC50 of 0.90 ± 0.10 μM. The findings were also
related to molecular docking studies, which provided models of strong interac-
tions with the EGFR-TK domain for the inhibitors. In cell cycle analysis, hybrid
6d caused a cell cycle arrest at the G1 transition phase.

Thiourea derivatives of uracil were efficiently synthesized via the reaction of 5-
aminouracil with isothiocyanates. Then, we prepared uracil-containing
thiazoles via condensation of thioureas with diethyl/dimethyl
acetylenedicarboxylates. The structures of the products were confirmed by a
combination of spectral techniques including infra-red (IR), nuclear magnetic
resonance (NMR), mass spectrometry (MS) and elemental analyses. A rationale
for the formation of the products is presented. The newly synthesized
compounds were evaluated for their in vitro antiproliferative activity against
four cancer cell lines. The compounds tested showed promising
antiproliferative activity, with GI50 values ranging from 1.10 μM to 10.00 μM.
Compounds 3c, 5b, 5c, 5h, 5i, and 5j were the most potent derivatives, with GI50
values ranging from 1.10 μM to 1.80 μM. Compound 5b showed potent
inhibitory activity against EGFR and BRAFV600E with IC50 of 91 ± 07 and 93 ±
08 nM, respectively, indicating that this compound could serve as a dual
inhibitor of EGFR and BRAFV600E with promising antiproliferative properties.
Docking computations revealed the great potency of compounds 5b and 5j
towards EGFR and BRAFV600E with docking scores of −8.3 and −9.7 kcal/mol
and −8.2 and −9.3 kcal/mol, respectively.

A series of new 1,3,4‐oxadiazole‐chalcone/benzimidazole hybrids 9a–o and 10a–k were designed and synthesized as potential antiproliferative agents. Hybrids 9a–o exhibited remarkable antiproliferative activities on different NCI‐60 cell lines in a single‐dose assay. The antiproliferative activities of the newly synthesized
compounds were evaluated against a panel of four human cancer cell lines
(A‐549, MCF‐7, Panc‐1, and HT‐29). Compounds 9g–i and their oxygen isosteres,
10f–h, exhibited promising antiproliferative activities with IC50 values ranging from
0.80 to 2.27 μM compared to doxorubicin (IC50 ranging from 0.90 to 1.41 μM).
Furthermore, the inhibitory potency of these compounds against the epidermal
growth factor receptor (EGFR) and BRAFV600E kinases was evaluated using erlotinib
as a reference drug. Molecular modeling studies were done to investigate the
binding mode of the most active hybrids in the ATP binding site of EGFR.

Some cyclooxygenase (COX)‐2 selective medications were withdrawn from the
market just a few years after their production due to cardiovascular side effects. In
this study, a new series of pyrimidine/thiazole hybrids 7a–p was synthesized as
selective COX‐2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and antiinflammatory
effects, and lower cardiotoxicity effects. The target compounds were
synthesized and in vitro tested against COX‐1, COX‐2, and sEH enzymes. Hybrids 7j,
7k, and 7i showed the greatest COX‐2‐inhibitory activity and were discovered to be
the most potent dual COX‐2/sEH inhibitors. In vivo tests revealed that these hybrids
were the most active analgesic/anti‐inflammatory agents, with improved ulcerogenic
and cardioprotective properties. Finally, the most active dual inhibitors were docked
into COX‐2/sEH active regions to explain their binding mechanisms.

A series of hybridized pyrrolidine compounds with a 1,2,4‐oxadiazole moiety were
synthesized to develop effective molecules against the enzymes DNA gyrase and
topoisomerase IV (Topo IV). Compounds 8–20 were developed based on a
previously disclosed series of compounds from our lab, but with small structural
modifications in the hopes of increasing the compounds' biological activity. In
comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase
inhibitory assay revealed that compounds 16 and 17 were the most potent of all
synthesized derivatives, with IC50 values of 180 and 210 nM, respectively.
Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV
of all the synthesized compounds, with an IC50 value of 13 μM, which was
comparable to novobiocin (IC50 = 11 μM). Therefore, hybrids 16 and 17 appeared to
be potential dual‐target inhibitors. In the minimal inhibitory concentration (MIC)
assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of
55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along
with the in vitro experiments, supports our promising approach to effectively
develop potent leads for further optimization as dual DNA gyrase and Topo IV
inhibitors.

A novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5 have been
synthesized, in good to excellent yields, via rapid base-catalyzed cyclization reaction of 2,4-dichloroquinoline-3-
carbonitrile (5) with guanidine hydrochlorides 6a-c. All the synthesized compounds were screened for their in
vitro antiproliferative activity. The most active hybrids 26a-d, 28a-d, and 30B were assessed against topoisomerase
(topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I
inhibitory activity while had weak topo IIα inhibitory action with compounds 30B and 28d, showed better topo I
inhibitory activity than the reference camptothecin. Compound 30B, the most potent derivative as antiproliferative
agent, exhibited moderate activity against CDK2 (IC50 = 1.60 μM). The results of this assay show
that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these
compounds is due to a different mechanism. Compounds 30B, 28d, and 28c were found to be the most potent
against EGFR and their EGFR inhibitory activities (IC50 = 0.40 ± 0.2, 0.49 ± 0.2, and 0.64 ± 0.3, respectively)
relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 μM). These results revealed that topo I and EGFR are
attractive targets for this class of chemical compound

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug
combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when
single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13–22
have been developed as dual EGFR and BRAFV600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19–22 demonstrating potent antiproliferative
activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV600E.
Compounds 15, and 19–22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were
superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of
BRAFV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity
comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and
BRAFV600E active sites to clarify their binding modes.

A new series of quinazoline-4-one/chalcone hybrids, 7–26 , was synthesized in this study as EGFR in- hibitors with antiproliferative activity. Target compounds were synthesized and in vitro tested against different cancer cell lines, EGFR, and BRAF enzymes. Three compounds showed the greatest antiprolif- erative activity and were the most potent EGFR inhibitors. Also, these three compounds improved the level of active caspase-3, 8, and 9 with potent induction of cytochrome c and Bax levels, as well as down regulation of Bcl - 2 levels. Finally, the most active inhibitors docked well inside EGFR active sites.

Recent studies have shown that combining kinase inhibitors has additive and synergistic effects. BRAF V600E and p38 αhave been extensively studied as potential therapeutic targets for a variety of dis- eases. In keeping with our interest in developing multi-targeted anticancer agents, a series of novel triaryl-imidazole-based analogues containing 3-aryl-1,2,4-oxadiazoles moiety ( 4a-h , Scaffold B) and their reaction intermediates aryl carboximidamides moiety ( 3a-h, Scaffold A) have been rationally designed, synthesized, and evaluated in vitro for their antiproliferative activity as dual p38 α/BRAF V600E inhibitors. The results revealed that the presence of the carboximidamide moiety is required for activity, and the best activity correlates with the Ar = 1,2-benzodioxole ( 3e ) ≥4-CH 3 O-C 6 H 5 -( 3c ) > 2-naphthyl (3h) > 4-Cl-C 6 H 5 ( 3b ). Ring closure of carboximidamide to 1,2,4-oxadiazole significantly reduces the activity. The results of docking study into p38 αrevealed higher binding affinities for compounds 3c, 3e , and 3h compared to the co-crystallized ligand, SB2. However, the docking study of compounds 3c and 3e into BRAF V600E revealed slightly lower affinities than vemurafenib.