Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Abstract

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...

Quinazoline Synthesis via Rh(III)-Catalyzed Intermolecular C–H Functionalization of Benzimidates with Dioxazolones

“…The quinazoline moiety, an abundant core of nitrogen-containing heterocycles, is exemplified as a privileged structure that exhibits diverse biological and therapeutic activities such as antibacterial, antiviral, anticonvulsant, and anticancer activities . For example (Scheme ), erlotinib (Tarceva) and gefitinib (Iressa) are well-known drugs used for the treatment of lung cancer.…”

Metal‐ and Catalyst‐Free Electrochemical Synthesis of Quinazolinones from Alkenes and 2‐Aminobenzamides

“…Quinazolinones possess multifarious bioactivities, consequently, they have been applied as the antibacterial, antifungal, antimalarial, anticancer, antihypertensive, antitubercular, and anticonvulsant agents (Scheme ). They are also important scaffold units of various natural products, such as Luotonin A, B, E and F, Rutaecarpine and Tryptanthrin, (Scheme ).…”

Accessing Polysubstituted Quinazolines via Nickel Catalyzed Acceptorless Dehydrogenative Coupling

“…Organo-heterocyclic compounds are one of the major building blocks/structural motifs in the pharmaceutical and agrochemical industries, and almost comprise more than 50% of all drug substances in therapeutic use (Figure ). Among them the quinazoline scaffolds, in particular, are very common structural motifs and are found in a large number of bioactive natural products and pharmacologically relevant compounds having antimicrobial, anticonvulsant, anti-inflammatory, antihypertensive, antitubercular, antimalarial, antiviral, and anticancer activities. Due to the prevalence of these scaffolds in drug discovery and medicinal chemistry, the development of new synthetic approaches for the synthesis of quinazoline derivatives continues to be a active field of research.…”