A novel group of indolyl‐1,2,4‐triazole‐chalcone hybrids was designed, synthesized,
and assessed for their anticancer activity. The synthesized compounds exhibited
significant antiproliferative activity. Compounds 9a and 9e exhibited significant
cancer inhibition with GI50 ranging from 3.69 to 20.40 μM and from 0.29 to
>100 μM, respectively. Both compounds displayed a broad spectrum of anticancer
activity with selectivity ratios ranging between 0.50–2.78 and 0.25–2.81 at the
GI50 level, respectively. The synthesized compounds were also screened for their
cytotoxicity by 3‐(4,5‐dimethylthiazole‐2‐yl)‐2,5‐diphenyltetrazol (MTT) assay and
for inhibition of epidermal growth factor receptor (EGFR) and c‐MET (mesenchymalepithelial
transition factor). Some of the tested compounds exhibited significant
inhibition against EGFR and/or c‐MET. Compound 9b showed the highest c‐MET
inhibition (IC50 = 4.70 nM) compared to foretinib (IC50 = 2.5 nM). Compound 9d
showed equipotent activity compared with erlotinib against EGFR (IC50 = 0.052 μM)
and displayed significant c‐MET inhibition with an IC50 value of 4.90 nM.

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual
or multi-targeted action, reducing drug resistance and adverse effects. A new series of
4-pyrazolylquinolin-2-ones (5a–j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors
were designed and synthesized. Compounds 5a–j were investigated for their cell viability effect against a
normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a–j
demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT
assay investigated the antiproliferative impact of targets 5a–j against four human cancer cell lines.
Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26,
29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover,
compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results
revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E
inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle
arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of −8.55 kcal mol−1 and −8.22 kcal mol−1, respectively. Furthermore, the ADME analysis of compounds 5a–j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.
 

A new series of 1,3,4-thiadiazin-3-ium bromide derivatives 9a–g were prepared as a six-member ring by
interactions between 4-substituted thiosemicarbazides 8a–e and a-halo ketones 2a,b. The reaction was
conducted using hydrazine-NH2 and yielded a hexagonal shape. The structures of all obtained
compounds have been verified using IR, NMR spectra, mass spectrometry, elemental analysis, and X-ray
crystallography. The X-ray crystallographic analysis of compounds 9a and 9b has revealed that the salt is
formed with the nitrogen atom N3 when the aromatic substituents 9a and 9d are present, but in the
case of compounds 9b, 9c, 9e, 9f, and 9g with the aliphatic substituent, the salt is formed outside the
ring. Compounds 9a–g were evaluated for antiproliferative activity as multitargeted inhibitors. Results
revealed that targets 9a–g displayed good antiproliferative activity, with GI50 ranging from 38 nM to
66 nM against a panel of four cancer cell lines compared to the reference Erlotinib (GI50 = 33 nM).
Compounds 9a, 9c, and 9d were the most potent antiproliferative derivatives, with GI50 values of 43, 38,
and 47 nM, respectively. Compounds 9a, 9c, and 9d were evaluated for their inhibitory activity against
EGFR, BRAFV600E, and VEGFR-2. The in vitro experiments demonstrated that the compounds being
examined exhibit potent antiproliferative properties and have the potential to function as multitargeted
inhibitors. In addition, the western blotting investigation demonstrated the inhibitory effects of 9c on
EGFR, BRAFV600E, and VEGFR-2.

We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR and
VEGFR-2 in the present study. Our study completely assesses the cytotoxic efficiency of pyrimidine-based derivatives 4−15 against various cancer cell lines, revealing derivatives 12 and 15 for their remarkable activity with GI50 values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro
enzyme assays showed that target compounds, particularly 12, 14, and 15, effectively inhibited EGFR and VEGFR-2. In vitro enzyme testing revealed that compound 15 was the most promising, with IC50 values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an in vitro assessment of the novel targets’ apoptotic potential revealed that both pro-apoptotic and antiapoptotic behaviors were promising, indicating that the apoptotic induction pathway is a strongly proposed action method for the newly developed targets. Finally, molecular docking experiments are elaborately discussed to corroborate the exact binding interactions of the most active hybrids 12 and 15 with the EGFR and VEGFR-2 active sites 

A series of 1,2,4-triazolo[1,5-a]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a−p with 3-phenyl-1,2,4-triazole-5-amine (5). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative,
Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds (9d, 9n, 9o, and 9p) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin’s 10−90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than
fluconazole’s 11.50−17.50 μM values. Compounds 9n and 9o, in particular, showed excellent bactericidal activity. Compounds 9n and 9o, the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that 9n and 9o demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference
drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds 9n and 9o demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of E. coli DNA gyrase and DHFR enzymes.

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h
demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional
assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50 μM and 5.80 μM, respectively. These results are much lower and more potent than
novobiocin’s IC50 value of 11 μM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a–j with antiinflammatory
properties have been developed and tested as dual mPGES-1/5-
LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j
were the most effective dual inhibitors of mPGES-1 and 5-LOX activities.
Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 μM
and 1.98 μM, respectively. In vivo, anti-inflammatory studies demonstrated that
compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with
EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib
after the first hour but exhibited stronger anti-inflammatory effects than
celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j
significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α,
and IL-6) with gastrointestinal safety profiles. Molecular docking simulations
explored the most potent derivatives’ binding affinities and interaction patterns
within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is
a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that
deserves further preclinical investigation.