RESEARCH ARTICLE Graph theoretical analysis, in silico modeling, prediction of toxicity, metabolism and synthesis of novel 2-(methyl/phenyl)- 3-(4-(5-substituted-1,3,4-oxadiazol-2-yl) phenyl) quinazolin-4 (3H)-ones as NMDA receptor inhibitor Govindaraj Saravanan 1 | Theivendren Panneerselvam 2 | Selvaraj Kunjiappan 3 | Pavadai Parasuraman 4 | Veerachamy Alagarsamy 1 | Padmaja Udayakumar 5 | Muthukrishnan Soundararajan 2,6 | Shrinivas D. Joshi 7 | Suresh Ramalingam 8 | Damodar Nayak Ammunje 9 Enabling Technologies Strategy, Management & Health Policy Hit, Lead & Candidate Discovery Preclinical Research & Development Clinical Research Post-Market Research 1 Department of Pharmaceutical Chemistry, MNR College of Pharmacy, Sangareddy, Telangana, India 2 Department of Pharmaceutical Chemistry, Karavali College of Pharmacy, Mangalore, Karnataka, India 3 International Research Center, Kalasalingam University, Krishnan Koil, Tamil Nadu, India 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India 5 Department of Pharmacology, Father Muller Medical College, Mangalore, Karnataka, India 6 Department of Pharmacology, Karavali College of Pharmacy, Mangalore, Karnataka, India 7 Department of Pharmaceutical Chemistry, Sonia Education Trust's College of Pharmacy, Dharwad, Karnataka, India 8 Department of Pharmacy, Annamalai University, Chidambaram, Tamil Nadu, India 9 Department of Pharmacology, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India Correspondence T. Panneerselvam, Department of Pharmaceutical Chemistry, Karavali College of Pharmacy, Vamanjoor, Mangalore 575028, Karnataka, India. Email: tpsphc@gmail.com Abstract A variety of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl)phenyl) quinazolin-4 (3H)-ones have been synthesized by treating 3-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)- 2-(methyl/phenyl)-quinazolin-4(3H)-one with a variety of secondary amines. Graph theoretical analysis was used in identification of drug target that is, NMDAR (N-methyl-D-aspartate recep- tors). The observed reports of in silico modeling and ligand based toxicity, metabolism prediction studies were encouraging us to synthesize of title compounds and evaluate their antiepileptic effects. The title compounds were tested for its antiepileptic potency by MES and scPTZ model. Rotorod test is used to assess its neurotoxicity. In the preliminary test it was found that in MES test, analogs 6d, 6e, 6f, and 6l were potent; whereas in scPTZ test analogs 6d, 6e, 6f, and 6k dis- played potent antiepileptic activity. Additionally these five derivatives were tested in rats orally at a dose of 30 mg/kg and found that compounds 2-methyl-3-(4-(5-morpholino-1,3,4-oxadiazol- 2-yl)phenyl)quinazolin-4(3H)-one 6e and 2-methyl-3-(4-(5-(piperidin-1-yl)-1,3,4-oxadiazol-2-yl) phenyl)quinazolin-4(3H)-one 6f exhibited superior activity than reference Phenytoin. In MES test, these derivatives 6e and 6f showed activity at 30 mg/kg i.p. dose after 0.5 hr and 4.0 hr. In scPTZ test these derivatives 6e and 6f showed activity at 100 and 300 mg/kg i.p. dose after 0.5 hr and 4.0 hr, respectively. KEYWORDS epilepsy, in silico modeling, in vivo studies, metabolism, neurotoxicity, oxadiazole, quinazoline, toxicity Received: 12 October 2018 Revised: 3 December 2018 Accepted: 15 December 2018 DOI: 10.1002/ddr.21511 Drug Dev Res. 2019;1–18. wileyonlinelibrary.com/journal/ddr © 2019 Wiley Periodicals, Inc. 1