C–N bond formation under Cu-catalysis: Synthesis and in vitro evaluation of N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones against chorismate mutase Raju Adepu a , K. Shiva Kumar a , Sandhya Sandra a , D. Rambabu a , G. Rama Krishna b , C. Malla Reddy b , Ajit Kandale a , Parimal Misra a , Manojit Pal a,⇑ a Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India b Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741252, India article info Article history: Received 9 June 2012 Revised 5 July 2012 Accepted 6 July 2012 Available online 16 July 2012 Keywords: Thienopyrimidinone Copper Coupling Chorismate mutase abstract A series of novel N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-ones were designed and synthesized as potential inhibitors of chorismate mutase. Synthesis of this class of compounds was carried out by using Cu-mediated C–N bond forming reaction between thieno[2,3-d]pyrimidin-4(3H)-ones and aryl boronic acids. The reaction can be performed in an open flask as the conversion was found to be not sensitive to the presence of air or atmospheric moisture. A range of compounds were prepared by using this method and single crystal X-ray diffraction study was performed using a representative compound. In vitro pharmacological data of some of the compounds synthesized along with dose response studies using active molecules are presented. In silico interactions of these molecules with chorismate mutase are also presented. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Pyrimidine nucleus fused with another heterocycle has been found to be an integral part of many natural products, agro chemi- cals and veterinary products. 1,2 This class of compounds has also found wide applications in the design and discovery of novel bioac- tive molecules and drugs. 3 Recently, thienopyrimidine I (Fig. 1) that belongs to this class has attracted considerable interest because of their various pharmacological properties such as antimicrobial, 4 antiviral, 5 anti inflammatory, 6 antidiabetic 7 and anticancer activi- ties. 8 Among thieno[2,3-d]pyrimidine derivatives, 3-amino-5,6-di- methyl-2-[4-(1-phenyl-methyl)-1-piperazinyl]thieno[2,3-d]pyr- imidin-4(3H)-one 9 II and 4-(4-methyl-1-piperazinyl)-2-methyl thio-6,7-dihydro-5H-cyclopenta [4,5]thieno[2,3-d]pyrimidine 10 III (Fig. 1) exhibited remarkable affinity and selectivity for the 5-HT3 receptor. Due to our continuing interest in the identification of no- vel anti-tubercular agents, 11 we became interested in exploring the N-aryl substituted thieno[2,3-d]pyrimidin-4(3H)-one C framework for the design of small molecules 12 as potential inhibitors of Myco- bacterium tuberculosis H37Rv chorismate mutase (CM). 13 Indeed, the framework C was derived from the general structure of inhibi- tors represented by A (reported by us earlier 11d ) via B (Fig. 2). In view of the fact that tuberculosis (TB) kills more than two million people a year worldwide and chorismate mutase being considered as a promising target for the development of anti tubercular agents the generation of a library of small molecules based on the frame- work C was undertaken. Preparation of N-aryl substituted thieno[2,3-d]pyrimidin- 4(3H)-one derivatives usually involves (i) the construction of the six membered pyrimidone ring by using 2-amino-N-aryl substi- tuted thiophene-3-carboxamide via a multi-step process 14a or (ii) condensation reaction of aryl amine with substituted thieno[2,3- d][1,3]oxazin-4-one. 14b,c However, all these methods require te- dious steps along with harsh reaction conditions and afforded the desired product in low yield. 14 Moreover, we required a more flexible, robust and high yielding method for the preparation of our target molecules based on C. Copper promoted C–N bond 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.07.011 ⇑ Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581. E-mail address: manojitpal@rediffmail.com (M. Pal). S N N N SCH 3 N S N N O N NH 2 N II III S N NH O I Figure 1. Thieno[2,3-d]pyrimidine (I) and its biologically active derivatives (II and III). Bioorganic & Medicinal Chemistry 20 (2012) 5127–5138 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc