In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds ( 6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a ) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI 50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas ( 12b, 12c and 13c ) with IC 50 s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds ( 7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.

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The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED 50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

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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.

A series of pyrazoline derivatives 2a-e, 3a-e and 4a-e structurally related to combretastatin A4 (CA-4) were synthesized and characterized by spectroscopic means and elemental analyses. In these compounds, the cis double bond of CA-4 was replaced with the pyrazoline ring aiming to enhance the cytotoxic effects displayed by CA-4 and to prevent the cis/trans isomerization that is associated with inactivation of CA-4. The cytotoxic activity of all new compounds was investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by the most active compounds 3d, 4a and e was evaluated. The cytotoxicity of 4e was correlated with induction of apoptosis and caspase-3 activation in vitro thus indicating the apoptotic pathway of anticancer effect of these compounds. Furthermore, in vivo evaluation of the synthesized compounds was carried out against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. Compounds 2c, 3a and e showed significant reduction in tumor weight, and about 2-4 fold increase in caspase-3 expression.

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