The reaction of 4-azido-quinolin-2(1H)-ones 1a–e with the active methylene compounds
pentane-2,4-dione (2a), 1,3-diphenylpropane-1,3-dione (2b), and K2CO3 was investigated in this
study. This approach afforded 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones 3a–j in high yields and
purity. All newly synthesized products’ structures were identified. Compounds 3a–j were tested
for antiproliferative activity against a panel of four cancer cell lines. In comparison to the reference
erlotinib (GI50 = 33), compounds 3f–j were the most potent derivatives, with GI50 values ranging
from 22 nM to 31 nM. The most effective antiproliferative derivatives, 3f–j, were subsequently
investigated as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Compound 3h
was the most potent inhibitor of the studied molecular targets, with IC50 values of 57 nM, 68 nM, and
9.70 nM, respectively. The apoptotic assay results demonstrated that compounds 3g and 3h function
as caspase-3, 8, and Bax activators as well as down-regulators of the antiapoptotic Bcl2, and hence can
be classified as apoptotic inducers. Finally, compounds 3g and 3h displayed promising antioxidant
activity at 10 M, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to
Trolox (77.6%)

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed
as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of
the new compounds was studied. 5c, 5d, 5f, 5g, 6e, and 6f have the highest antiproliferative activity with GI50
values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 ¼ 33nM). Compounds 5d,
5f, and 5g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM.
Moreover, compounds 5f and 5g had the most potent inhibitory activity against EGFRT790M with IC50 values of
9.5± 2 and 11.9 ±3nM, respectively, being equivalent to the reference osimertinib (IC50 ¼ 8±2nM).
Compounds 5f and 5g demonstrated excellent caspase-3 protein overexpression levels of 560.2±5.0 and
542.5±5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2±4.0 pg/mL). they
also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein.
Computational docking studies supported the enzyme inhibition results and provided favourable dual binding
modes for both compounds 5f and 5g within EGFRWT and EGFRT790M active sites. Finally, in silico
ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds

Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAFV600E inhibitors have
been developed. The target compounds were synthesized and tested in vitro against four cancer
cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values
of 1.05 M, 1.50 M, and 1.20 M, respectively. Hybrids showed dual inhibition of EGFR and
BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising
anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and
BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and
resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that
compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in
silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and
adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The
values of the HOMO and LUMO energies, as well as softness and hardness, were computationally
investigated using the DFT method. These findings agreed well with those of the in vitro research
and molecular docking study

In this article, we display on the synthesis and biological evaluation of a new series of
thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new
compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy
in addition to elemental analyses. The cell viability of the new compounds was assessed
against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none
of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds
examined at 50 mM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated
against four human cancer cell lines where the compounds showed promising activity. The
most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI50 values ranging from

A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting
EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib.
Hybrids VIc, VIf, VIg, VIi, and VIk have the highest antiproliferative activity. Compounds VIc, VIf, VIg,
VIi, and VIk inhibited EGFR with IC50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the
most potent inhibitory activity as BRAFV600E (IC50 ¼ 49 and 40 nM, respectively) and were discovered to
be potent inhibitors of cancer cell proliferation (GI50 ¼ 44 and 35 nM against four cancer cell lines,
respectively). Compound VIk, the most effective derivative as an antiproliferative agent, demonstrated
potent anti-CDK2 action with an IC50 value of 12 nM, which is 1.5-fold more potent than the reference
dinaciclib. Finally, VIc, VIf, and VIk have a high capacity to inhibit LOX-IMVI cell line survival

Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6–10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a–c to 17a–c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines. The results clearly show that 5-arylidenethiazolin-4-one moiety contributes substantially to the activity. Also, methyl esters are more potent than amides, while N-ethylamides are the most potent among amides. 14b showed the highest potency against all tested cancer cell lines with IC₅₀ 1.4–2.5 µM, while against normal cell line IC₅₀ > 50 µM. It showed arrest of HeLa cells at G0/G1, S p

This study explores the synthesis of pyrimidine heterocycles 9–29. The exact structure was determined and confirmed by NMR, HRMS, and X-ray diffraction investigation. Compounds 9–29 were evaluated as dual inhibitors of EGFR and VEGFR-2 in order to develop a scaffold capable of stopping cell growth. The findings indicated that compounds 22 and 29 are potential apoptotic antiproliferative agents that inhibit EGFR and VEGFR-2. Molecular docking studies have clearly shown how compounds 22 and 29 bind to the active sites of EGFR and VEGFR-2. This comprehensive examination is essential for comprehending their mechanism of action as antiproliferative agents. Moreover, the in-depth study of these hybrids’ absorption, distribution, metabolism, and excretion (ADME) features shows how useful they could be as therapeutic agents.

Conversely, additional structural modifications may be necessary to effectively obtain more potent lead molecules for the development of future cancer therapeutics.

Bioassay-guided fractionation approach led to identification of two novel compounds; (4-(hydroxymethyl)-3-methoxy-1H-pyrazol (1) and mycalene (2), alongside with four known metabolites; octadecane (3), hexatriacontane (4), 1-heneicosanol (5) and heptatriacontanoic acid (6) from the Red Sea marine sponge Hemimycale sp. The ethyl acetate fraction showed a noticeable cytotoxic activity against the lung cancer cell line (A549) with IC₅₀ value of 75.54 µg/ mL. Structural elucidation was achieved using a combination of 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS). To elucidate the potential mechanism of action behind the cytotoxic effects against lung cancer, a multi-faceted approach combining in silico network pharmacology, experimental validation, and molecular docking studies were employed. Both compounds …

A novel set of quinazoline-4-one/1,2,4-oxadiazole hybrids (9a-o) was designed and synthesized as EGFR, EGFR^T790M, and BRAF^V600E inhibitors in the search for multitargeted antiproliferative scaffold. The novel hybrids showed encouraging antiproliferative actions. Compounds 9b, 9c, 9h, 9k, and 9l were evaluated as EGFR and BRAF^V600E inhibitors. These in vitro experiments demonstrated that compounds 9b, 9c, and 9h are potent antiproliferative agents capable of acting as dual EGFR/BRAF^V600E inhibitors. 9b, 9c, and 9h were further studied for their inhibitory effect on mutant EGFR (EGFR^T790M), with the results indicating that the evaluated compounds had a significant inhibitory effect. Cell cycle analysis and apoptosis induction assay of 9b revealed cell cycle arrest at the G2/M phase, which can induce apoptosis. EGFR and BRAF^V600E docking simulations inside their active regions shed light on these compounds’ possible modes of inhibition. ADME calculations revealed that all test compounds satisfy Lipinski’s rule of five (RO5) with MLogP <5, with easy transport through cell membranes and higher oral bioavailability. These new hybrids may have potential as anti-cancer drugs after optimization.

A novel series of 1,2,3-triazole/quinazoline-4-one hybrids (8a–t) were designed and synthesized as dual-targeted antiproliferative agents. Compounds 8a–t were evaluated for their antiproliferative efficacy against a panel of four cancer cell lines. The results indicated that most of the evaluated compounds exhibited strong antiproliferative activity, with 8f, 8g, 8h, 8j, and 8l demonstrating the highest potency. These five compounds were investigated as EGFR and BRAFV600E inhibitors. The in vitro tests showed that compounds 8g, 8h, and 8j are strong antiproliferative agents that might work as dual EGFR/BRAFV600E inhibitors. Compounds 8g and 8h were further examined as activators of caspases 3, 8, and Bax and down-regulators of the anti-apoptotic protein Bcl2. The results indicated that the studied compounds had considerable apoptotic antiproliferative action. The investigation of the cell cycle and apoptosis …