Nadia A. Khalil

Synthesis and anticonvulsant activity of new phenytoin derivatives.

Hybrids between phenytoin and thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole or 1,2,4-triazole were synthesized and tested for anticonvulsant activity. Preliminary anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. The neurotoxicity was determined applying the rotarod test. Among these compounds, 4 and 5d showed the highest protection (80%) in the scPTZ test at a dose of 100 mg/kg, whereas the compound 5b displayed promising anticonvulsant effect in the MES model.

Synthesis of novel isatin-thiazoline and isatin-benzimidazole conjugates as anti-breast cancer agents.

A series of new isatin-thiazoline 3a–h and isatin-benzimidazole 4a–h derivatives were synthesized via condensation of isatin Mannich bases 2a–h with either 2-aminothiazoline or 2-aminobenzimidazole. The structures of the newly synthesized compounds were characterized by spectral data. The anti-breast cancer activity of some of the synthesized compounds was assessed in the MCF-7 human breast cancer cell line. The results showed that compounds 4b, 4d and 4g possess significant antiproliferative activity against MCF-7 cells.

Structure-based molecular design, synthesis, and in vivo anti-inflammatory activity of pyridazinone derivatives as nonclassic COX-2 inhibitors

A scaffold with bicyclic core carrying pyridazinone moiety, which exhibited potent in vivo anti-inflammatory activities, was introduced in this article. The design of these compounds was assisted by docking and superposition experiments on cyclooxygenase-2 enzyme. The activity of a chloro analogue was as high as that of diclofenac in carrageenan-induced rat paw edema anti-inflammatory screening.

Synthesis and anti-inflammatory activity of novel pyridazine and pyridazinone derivatives as non-ulcerogenic agents

Herein, we report the synthesis and pharmacological properties of several series of pyridazine and pyridazinone derivatives. All the synthesized compounds were tested, in vivo, for their anti-inflammatory and ulcerogenic properties against indomethacin, as a reference compound. Compounds 4a and 9d have shown a potent anti-inflammatory activity more than indomethacin with rapid onset of action and safe gastric profile. The latter compounds were then selected for further investigation. In the MTT assay in vitro, both compounds were identified as potent and selective COX-2 inhibitors.

Synthesis and biological evaluation of new pyrazolone-pyridazine conjugates as anti-inflammatory and analgesic agents.

A new series of pyrazolone-pyridazine conjugates 3 and 4a-l were synthesized and characterized by spectroscopic means and elemental analyses. All compounds were tested in vivo for their anti-inflammatory and analgesic properties against diclofenac, as reference compound. The synthesized compounds were also evaluated for their ability to inhibit the production of certain inflammatory cytokines such as TNF-α and IL-6 in serum samples. The ulcerogenic potential of the synthesized compounds was also determined. IC50 values for inhibition of COX-1 and COX-2 enzymes were investigated in vitro for the most active candidates. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Among the synthesized derivatives, compounds 4c and 4e showed good analgesic and anti-inflammatory activities with lower ulcer index than the reference drug.

Synthesis and biological evaluation of novel pyrazoline derivatives as anti-inflammatory and antioxidant agents

A series of novel 5-aryl-3-cyclopropyl-4,5-dihydropyrazole derivatives 2a–p were synthesized via cyclization of chalcones 1a–h with thiosemicarbazide or semicarbazide HCl and evaluated as anti-inflammatory/antioxidant agents. The structures were confirmed by elemental analyses and spectral data. The free radical scavenging activity toward superoxide was determined. Their effect on hepatocytes viability and nitric oxide (NO) production in LPS-stimulated macrophages was also determined. The results showed that compounds 2e and 2n demonstrated the highest free-radical scavenging and anti-inflammatory activities, thus can be useful in the prevention of oxidative stress and inflammation-related disorders.

Design, Synthesis, and Antitumor Activity of Novel 5-Pyridyl-1,3,4-oxadiazole Derivatives against the Breast Cancer Cell Line MCF-7.

Various 1,3,4-oxadiazole-2-thiol derivatives have considerable potential in the field of antitumor activity. On the basis of the structure of the highly active reported oxadiazole analogues, 36 novel compounds were designed. Their molecular transport properties were predicted using a computer-aided program, and they were then synthesized and tested for anticancer activity against the breast cancer cell line MCF-7. Most of the tested compounds showed excellent to potent cytotoxic activity. Docking studies were carried out to examine the possibilities of the target compounds to become lead compounds in the future after more biological investigations. Compounds 18 and 22 were more active than the reference drug with IC₅₀ values of 0.010 µM and 0.012 µM, respectively, and binding energy scores of -10.32 and -10.25, respectively.

4-Substitutedphthalazines and phthalazinones: synthesis, characterization and β-adrenergic blocking activity

Novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-propanol spacer to N-substituted piperazine residue were synthesized. All the new compounds were screened for their effect on β-adrenergic blocking activity on the norepinephrine-induced precontracted aortic ring module. Most test compounds displayed appreciable β-adrenolytic activity compared to propranolol as a reference standard. The results have shown that compounds 3a, 3d, 3e and 7c displayed appreciable inhibition of norepinephrine-induced aortic ring contraction.Graphical AbstractA novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-propanol spacer to N-substituted piperazine residue were synthesized. All new compounds were screened for their effect on β-adrenergic blocking activity on the norepinephrine-induced precontracted aortic ring module.

Synthesis and cytotoxic activity of certain trisubstituted azetidin-2-one derivatives as a cis-restricted combretastatin A-4 analogues

Novel series of 1,3,4-trisubstituted azetidin-2-one derivatives 8a–p were synthesized and proposed as cytotoxic agents acting via inhibition of tubulin at the colchicine binding site. The design of the target compounds was based upon modification in the structure of the vascular targeting agent combretastatin A-4 (CA-4). The cis double bond linker in CA-4 was replaced with the azetidin-2-one ring aiming to prevent the cis/trans isomerization that suppresses the activity of CA-4, thereby enhancing its antiproliferative activity. All new compounds were investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by four most potent compounds 8g, 8j, 8n and 8o was also evaluated. The synthesis of the final targets was achieved adopting Staudinger reaction. Molecular modeling studies were performed to rationalize the biological results.

New 3‐Substituted‐2‐(4‐hydroxyanilino)pyridine Derivatives: Synthesis, Antitumor Activity, and Tubulin Polymerization Inhibition

A series of new pyridine derivatives 4a–c, 5a–d, 6a–d, 7a–f, and 8a–f structurally related to ABT‐751 were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were tested for their cytotoxic activity in vitro against the HCT‐116 and HepG‐2 cancer cell lines using the MTT assay. The results showed that compound 8d has higher cytotoxic activity than the reference antimitotic agent colchicine, against both tested cell lines, with IC50 = 0.52 and 1.40 μM, respectively. The three most active compounds, 5d, 8b, and 8d, were further screened in vitro for inhibition of tubulin and showed remarkable results in comparison to colchicine.