ARTICLE Synthesis, anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives Irum Shahzadi 1 | Ameer F. Zahoor 1 | Azhar Rasul 2 | Nasir Rasool 1 | Zohaib Raza 3 | Shahla Faisal 4 | Bushra Parveen 1 | Shagufta Kamal 5 | Muhammad Zia-ur-Rehman 6 | Faisal M. Zahid 4 1 Department of Chemistry, Government College University Faisalabad, Faisalabad, Pakistan 2 Department of Zoology, Government College University Faisalabad, Faisalabad, Pakistan 3 Department of Pharmacology, Government College University Faisalabad, Faisalabad, Pakistan 4 Department of Statistics, Government College University Faisalabad, Faisalabad, Pakistan 5 Department of Biochemistry, Government College University Faisalabad, Faisalabad, Pakistan 6 Applied Chemistry Research Centre, PCSIR Laboratories Complex, Lahore, Pakistan Correspondence Ameer F. Zahoor, Department of Chemistry, Government College University Faisalabad, 38000 Faisalabad, Pakistan. Email: fawad.zahoor@gcuf.edu.pk; fawad. zahoor@gmail.com Abstract Theophylline-7-acetic acid (acefylline) (3) and its derivatives are pharmacologi- cally active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of 2-((5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)- yl)methyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamides (10a-j) has been reported. All the synthesized derivatives (10a-j) were structurally verified by FT-IR, 1 H NMR, 13 C NMR and evaluated for their anti-cancer (using MTT assay), hemolytic and thrombolytic potential. N-(4-Chlorophenyl)-2-(5-((1,- 3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2- ylthio)acetamide (10g) was found to be the most active against human liver cancer cell lines (Huh7) having cell viability 53.58 ± 1.28 using 100 μg/mL concentration of compound which was further in-silico modelled to describe the possible mechanistic insights for its anti-proliferative activity. The results of hemolytic and thrombolytic activities indicated that these derivatives were less toxic and hold considerable potential as a drug candidate. 2-(5-((1,3- Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2- ylthio)-N-(2-fluorophenyl)acetamide (10c) of the series was found to be least toxic with 0.1% hemolysis relative to ABTS (95.5%) as positive control. 2-(5- ((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol- 2-ylthio)-N-(tetrahydro-2H-pyran-4-yl)acetamide (10j) exhibited potent clot lysis activity (90%) as compared to negative control DMSO (0.57%). 1 | INTRODUCTION Purine based natural products produce a variety of biologi- cally and pharmacologically active derivatives via structural modifications. [1] Various purine-based drugs are currently used for the treatment of different diseases including respiratory and neurodegenerative diseases, cancer, and diabetes. [2] Theophylline is a purine-based xanthene which exhibits multidimensional biological and pharmacologi- cal properties. [3] 7, 8-disubstituted theophylline act as hypotensive agents on cardiovascular system, [4,5] whereas its alkyl substituted derivatives in 7- and 8-positions increase its activity at adenosine receptors and act as anti- cancer, anti-microbial, anti-inflammatory, and vascular relaxing agents [6,7] (Figure 1). Some of its derivatives are found active against hyperglycemia which causes diabetic complications in NIDDM (noninsulin dependent diabetes mellitus) patients. [8] Its amide and Schiff base derivatives have been reported as bronchodilators for therapy of respiratory diseases like chronic pulmonary disease or Received: 30 September 2019 Revised: 6 February 2020 Accepted: 18 March 2020 DOI: 10.1002/jhet.3987 J Heterocyclic Chem. 2020;1–13. wileyonlinelibrary.com/journal/jhet © 2020 Wiley Periodicals LLC 1