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.

New quinoline-based derivatives 3a-d and 4a-d have been designed and synthesized as promising antiproliferative candidates. The designed compounds were tested for their antiproliferative activity against a panel of four human cancer cell lines with GI50 values ranging from 1.40 μM to 5.00 μM relative to doxorubicin (GI50 = 1.20 μM). Compound 4a was the most potent derivative against the four examined cancer cell lines (GI50 = 1.40 μM) relative to the reference doxorubicin (GI50 = 1.20 μM), indicating the role of the oxime moiety in the
antiproliferative activity. The inhibitory impact on EGFR and BRAFV600E as potential molecular targets was
investigated for the most effective antiproliferative derivatives, 3c, 4a, and 4b. Compound 4a exhibited the
highest EGFR and BRAFV600E inhibitory activity with IC50 values of 105±10 nM and 140±12 nM, respectively,
which is comparable to the reference erlotinib with IC50 values of 80±10 nM and 60±10, respectively. Docking
computations were utilized to analyze the docking modes and scores of compounds 3c, 4a, and 4b with respect
to EGFR and BRAFV600E. The results of the docking computations revealed a favorable affinity of compound 4a
towards both EGFR and BRAFV600E, with values of -7.05 kcal/mol and -7.67 kcal/mol, respectively