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In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC 50 ¼ 0.16-34.13 lM). The drug-likeness study revealed that all the new compounds conform to Lipinski's rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G 1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC 50 ¼ 25.53-115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.

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In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC 50 in the range of 0.52-6.26 lM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC 50 ¼0.155-17.08 lM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents. HIGHLIGHTS 1. Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized. 2. Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines. 3. Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d. 4. Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization. 5. Compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. 6. Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.

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Series of 2,3-disubstituted quinazolinone derivatives and a [1,2,4]triazino[2,3-c]quinazolinone featuring the pharmacophoric elements of anticonvulsant drugs were designed and synthesized. Target compounds were screened for their anticonvulsant activity using the subcutaneous pentylenetetrazole (s.c. PTZ) and maximal electroshock (MES) models. The s.c. PTZ test showed that the most active compound was the amide derivative 9c having a protective dose 50 (PD 50 ) of 200.53 µmol/kg (PD 50 of phenobarbitone=62.18 µmol/kg); nevertheless, this low potency is outweighed by the much higher safety profile of 9c (LD 50 >3000 mg/kg). In the MES screening, seven compounds were equal to or more active than phenytoin; some of these compounds were less neurotoxic than phenytoin. Few compounds such as 9c and 10 were effective in both models. LD 50 for the most active compounds was calculated.Key words quinazolinone; pentylenetetrazole model; maximal electroshock model; anticonvulsant activity; LD 50 ; neurotoxicity Epilepsy is an all-pervading neurological disorder characterized by recurrent seizures and affecting about 1% of the world's population. In the last few decades, many efforts devoted for the development of novel therapeutics resulted in the availability of several newer agents as promising anticonvulsants.1,2) The efficacy of many of the marketed antiepileptic drugs is greatly compromised by severe side effects such as ataxia, drowsiness, gingival hyperplasia, gastrointestinal disturbances, and megaloblastic anaemia. Moreover, about 30% of patients have uncontrolled seizures.3-8) Therefore, continued search for safer and more effective anticonvulsants is urgently necessary.The insufficient information on the cellular mechanism of epilepsy in human and the complex mechanism of action of most of the antiepileptic drugs makes it difficult to use rational methodologies in the discovery of new antiepileptic drugs. Therefore, another design approach based on the existence of different pharmacophores that were established through the analysis of structural characteristics of clinically effective drugs as well as other antiepileptic compounds was adopted.9-11) In the literatures, it is well documented that one of the important core fragments is defined by the presence of: i) hydrogen donor/acceptor unit (HAD), ii) one electron donor atom (D), and iii) a hydrophobic domain (A) (aryl ring substituted/unsubstituted).12-15) These structural features were found in the first generation drugs including the well-established antiepileptics such as carbamazepine or phenytoin, and the newest drugs e.g., Felbamate; and in the second generation antiepileptic drugs and the drugs in clinical trial (Fig. 1). Efforts devoted in the recent years based on this pharmacophore model resulted in the availability of several newer drugs (such as retigabine, tiagabine, lamotrigine, pregabalin, stiripentol, zonisamide, topiramate, levetiracetam) as promising antiepileptics. 1)Literature survey revealed that quinazoline is a privileged lead molecule fo...

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