Nahla Ahmed Farag

1. AbstractIn this study, 12 novel 2-amino-4-thiazolidinone derivatives (IIIa-l) were designed and synthesized as novel anti-cancer agents. All newly synthesized compounds are submitted to be evaluated for their antiproliferative activity on MCF-7 cell line at initial dose of 10 µM. Compounds IIIi, IIIl and IIIj showed remarkable inhibitory activity of 85.9%, 75.4% and 67%, respectively. Five compounds were selected to be further evaluated for their ability to inhibit estrogen receptor alpha (ERα) at 10 µM, using western blot assay on MCF-7 cell line and tamoxifen as positive control. Compounds IIIl (NO2), IIIk (2-OCH3) and IIIj (3-Br) demonstrated a significant inhibition of ERα expression with values 0.17,0.17 & 0.18, respectively. Molecular docking studies were carried out against ERα (PDB ID: 3ERT) to study its orientation, binding affinity and interactions, Molecular dynamics simulations of compounds IIIl, IIIk and IIIj at 100 ns against ERα confirmed the stability of the protein-ligand complexes, generating a 1000-frame trajectory with 100 ps intervals. The trajectories were analyzed using AMBER scripts to calculate RMSD, RG and RMSF values. The results confirmed that the stability of the complexes formed by the selected compounds with ERα throughout the simulation period, supporting their potential as promising candidates for ERα inhibition. Computer-aided ADMET was performed, where IIIl emerged as lead candidate as it exhibited optimal ADME profile with favorable lipophilicity and polar surface area.

Undecaprenyl Pyrophosphate Synthase (UPPS) is a vital target enzyme in the early stages of bacterial cell wall biosynthesis. UPPS inhibitors have antibacterial activity against resistant strains such as MRSA and VRE. In this study, we used several consecutive computer-based protocols to identify novel UPPS inhibitors. The 3D QSAR pharmacophore model generation (HypoGen algorithm) protocol was used to generate a valid predictive pharmacophore model using a set of UPPS inhibitors with known reported activity. The developed model consists of four pharmacophoric features: one hydrogen bond acceptor, two hydrophobic, and one aromatic ring. It had a correlation coefficient of 0.86 and a null cost difference of 191.39, reflecting its high predictive power. Hypo1 was proven to be statistically significant using Fischer’s randomization at a 95% confidence level. The validated pharmacophore model was used for the virtual screening of several databases. The resulting hits were filtered using SMART and Lipinski filters. The hits were docked into the binding site of the UPPS protein, affording 70 hits with higher docking affinities than the reference compound (6TC, − 21.17 kcal/mol). The top five hits were selected through extensive docking analysis and visual inspection based on docking affinities, fit values, and key residue interactions with the UPPS receptor. Moreover, molecular dynamic simulations of the top hits were performed to confirm the stability of the protein–ligand complexes, yielding five promising novel UPPS inhibitors. Graphical Abstract

A new series of indolyl 1,2,4-triazole scaffolds was designed, synthesised, and biologically evaluated for their inhibitory activity against both CDK4 and CDK6. The results ranged from 0.049 μM to 3.031 μM on CDK4 and from 0.075 μM to 1.11 μM on CDK6 when compared to staurosporine, with IC₅₀ values of 1.027 and 0.402 μM, respectively. Moreover, all compounds were tested for their cytotoxicity against two breast cancer cell lines, MCF-7 and MDA-MB-231. All of the synthesised compounds showed promising anti-proliferative activity, with two compounds Vf (IC₅₀ = 2.91 and 1.914 μM, respectively) and Vg (IC₅₀ = 0.891 and 3.479 μM, respectively) having potent cytotoxic activity in comparison to the reference staurosporine (IC₅₀ = 3.144 and 4.385 μM, respectively). Vf and Vg were also found to significantly induce apoptosis to 45.33% and 37.26% (control = 1.91%) where Vf arrested the cell cycle at the S phase while Vg arrested the cycle at the G₀/G₁ phase. The binding mode and interactions of all compounds were studied and found to mimic those of the FDA approved CDK4/6 inhibitor palbociclib that was used as a reference throughout the study.

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone‐privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase‐2 (COX‐2)/5‐lipoxygenase (5‐LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5‐LOX inhibitory activity and COX‐2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti‐inflammatory activity. Compound 3j was found to be the most promising derivative, with IC₅₀ values of 667 and 47 nM against COX‐1 and COX‐2, respectively, which are superior to that of celecoxib (IC₅₀ value against COX‐2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX‐1 inhibition, with IC₅₀ values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5‐LOX, with IC₅₀ values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC₅₀ values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC₅₀ = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti‐inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX‐2 and 5‐LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX‐2 and 5‐LOX as dual inhibitors, as a new avenue in anti‐inflammatory therapy.

Four novel series of 1-substituted-3-(2-methyl-4-oxo-4H-quinazolin-3-yl) urea and/or thiourea IIIa–c, 4-substituted-N-(2-methyl-4-oxo-4H-quinazolin-3-yl) benzene sulfonamide VIa–c and their NO-hybrid molecules as nitrate esters Va–c and VIIIa–c have been synthesized and evaluated for their anti-inflammatory activity in vivo and in vitro. Moreover, the nitrate ester derivatives Va–c, VIIIa–c have been assayed for the release of nitric oxide in serum using the Griess diazotization method by a nitric oxide detection kit, and the results were correlated with their gastric protective activity through the determination of the ulcer index, and histopathological investigations of the gastric mucosa under a light microscope. All of the tested compounds showed potent to moderate anti-inflammatory activity when compared to the reference drug Meloxicam. In the comparison of IIIb and its nitrate ester Vb, for the COX-2 inhibition assay, IIIb showed IC₅₀ = 5 μM, and Vb showed IC₅₀ = 6.86 μM with a selectivity index of 4.74 and 5.03, respectively. As for the IC₅₀ of the COX-1 assay, it was found that the structures carrying nitric oxide moieties had less affinity to inhibit COX-1 than their corresponding starting intermediates, as in the case of compound IIIb that showed IC₅₀ = 23.76 μM, and its nitrate ester Vb that showed IC₅₀ = 34.6 μM; hence, it can be concluded that the alcoholic metabolites of NO esters had less tendency to inhibit COX-1, leading to less gastric ulcerative side effects. This was confirmed by measuring the nitric oxide amount release from Vb, which was found to be 28.53 μmol L⁻¹ with the lowest ulcer index of 0.4, showing the least tendency to induce stomach ulcerations in rats. According to these results, we can conclude that quinazoline derivatives with nitric oxide release moiety seem potentially attractive as preferential COX-2 inhibitors.