New indole/1,2,4-triazole hybrids were synthesized
and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization
inhibitors. Methods: All final compounds, 6a–j and 7a–j were evaluated at a single
concentration of 10 μM against a panel of sixty cancer cell lines. Results: Compounds 7a–j,
featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their
precursor ketones 6a–j across all tested cancer cell lines. Compounds 6h, 7h, 7i, and 7j
were chosen for five-dose evaluations against a comprehensive array of 60 human tumor
cell lines. The data showed that all tested compounds had significant anticancer activity
throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to
2.29 at the GI50 level. Compounds 7h and 7j showed substantial anticancer effectiveness
against most cell lines across nine subpanels, with GI50 values ranging from 1.85 to 5.76 μM
and 2.45 to 5.23 μM. Compounds 6h, 7h, 7i, and 7j were assessed for their inhibitory
effects on tubulin polymerization. Conclusions: The results showed that compound 7i, an
oxime-based derivative, was the most effective at blocking tubulin, with an IC50 value of
3.03 ± 0.11 μM. This was compared to the standard drug CA-4, which had an IC50 value of
8.33 ± 0.29 μM. Additionally, cell cycle analysis and apoptosis assays were performed for
compound 7i. Molecular computational investigations have been performed to examine
the binding mode of the most effective compounds to the target enzyme.

A novel series of 5-ethylsulfonyl-indazole-3-carbohydrazides 7a–o, serving as dual inhibitors of EGFR
and VEGFR-2 was developed. The antiproliferative effects of compounds 7a–o were assessed against
four cancer cell lines via the MTT assay. Compounds 7g, 7i–7l, and 7o emerged as the most efficient
six derivatives, with GI50 values ranging from 25 nM to 42 nM. Compounds 7j, 7k, and 7o (GI50 values
of 27, 25, and 30, respectively) demonstrated greater potency than erlotinib (GI50 value of 33 nM),
particularly against breast (MCF-7) cancer cell lines, and were identified as the most potent dual
EGFR/VEGFR-2 inhibitors. Apoptotic markers assay results showed that increased levels of p53 and
Bax proteins, along with lower levels of antiapoptotic Bcl-2, govern the apoptosis process in these
new compounds. Computational analyses, encompassing molecular docking, molecular dynamics
(MD) simulations, and density functional theory (DFT) computations, elucidated the binding
interactions of these drugs with EGFR and VEGFR-2.

Molecular hybridization of substituted 2-phenylbenzimidazole and pyridine moieties afforded a new series of
antimalarial targeting compounds 5a-l. They were assessed against both chloroquine resistant -W2 (CR-W2) and
chloroquine sensitive-D6 (CS-D6) strains of P. falciparum. Artemisinin and chloroquine were used as standards
drugs. Results revealed that compounds 5e, 5j, 5k and 5l were the most effective against CS-D6 P. falciparum
strain with IC50 values ranged between 0.019 and 0.056 μM and selectivity index values of 7551.95–13642.10. In
addition to 5j and 5k derivatives, another four tested compounds 5c, 5d, 5f and 5g exerted effective antimalarial
activity against CR-W2 strain of P. falciparum, their IC50 values were between 0.046 and 0.253 μM with high
selectivity index values ranged from 2610.23 to 1024.50. Upon assessing DHFR inhibitory activity of the energetic
derivatives, compounds 5j, 5k, and 5e exhibited IC50 values of 0.72, 3.95, and 5.31 μM, respectively, in
comparison to the reference medication trimethoprim, which has an IC50 of 13.36 μM. Moreover, molecular
dynamic simulations and docking experiments were applied to the most active derivative, 5j, into the catalytic
binding site of wild-PfDHFR–TS, were done and showed interesting binding profiles and affinities. Furthermore,
in silico physicochemical and pharmacokinetic parameters were predicted.

A new series of benzimidazole–oxadiazole-small molecules were synthesized and confirmed with various spectroscopic
techniques. The prepared derivatives exhibited significant inhibitory activity against the proliferation
of different cancer cells. The benzimidazoles 10f, 10 h, 10 g, and 10i showed broad anticancer activity with no
selectivity in five-dose assays. All prepared compounds displayed potent inhibitory activity against proliferation
of a panel of four human cancer cells (HT-29, Panc-1, MCF-7, and A-549) with IC50 values ranging from 24 nM to
80 nM and with significant safety profile against MCF-10 A normal cells. According to the mechanistic study, the
most potent compounds (9a, 9b, 10e, 10f, & 10i) displayed remarkable inhibitory effectiveness against EGFR
and BRAFV600E and were more potent than reference drugs erlotinib and vemurafenib. Molecular docking study
for compounds 9a, 9b, 10e, 10f, and 10i agreed with mechanistic results.