Original article 1,3-dihydro-2H-indol-2-ones derivatives: Design, Synthesis, in vitro antibacterial, antifungal and antitubercular study Tarunkumar Nanjibhai Akhaja, Jignesh Priyakant Raval * Department of Pharmaceutical Chemistry, Ashok & Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences (ARIBAS), New Vallabh vidyanagar, Gujarat 388121, India article info Article history: Received 5 August 2011 Received in revised form 9 September 2011 Accepted 15 September 2011 Available online 22 September 2011 Keywords: 1,3-dihydro-2H-indol-2-ones MCRs (Multicomponent Reactions) Biginelli reaction CaCl 2 catalyst in vitro antituberculer activity Antimicrobial activity abstract 1,3-dihydro-2H-indol-2-ones derivatives are reported to exhibit a wide variety of biodynamic activities such as antituberculer, anti HIV, fungicidal, antibacterial, anticonvulsant. These valid observations led us to synthesize some new indole-2-one derivative. Thus, herein we report synthesis of various 5- substituted-3-[{5-(6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4 tetrahydro pyrimidin-5-yl)-1,3,4-thiadiazol- 2-yl}imino]-1,3-dihydro-2H-indol-2-one derivatives 4ael using one pot multicomponenteBiginelli reaction via CaCl 2 catalyst. Structures and purity of these compounds were confirmed by elemental, IR, ( 1 H& 13 C) NMR and Mass spectral analysis. Newly synthesized compounds were also tested for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H 37 Rv, in vitro antibacterial activity against selected human pathogens viz. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Staphylococcus aureus, Staphylococcus pyogenus, Bacillus subtilis and antifungal activity against Candida albicans, Aspergillus niger, Aspergillus clavatus strains. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Drug discovery and development is a very laborious and costly process involving synthesis and screening of diverse organic compounds. In this regard, multicomponent reactions (MCRs) are of increasing importance in the field of medicinal chemistry [1e3]. Currently, attention is put on speed, diversity, and efficiency in the drug discovery process [4]. MCRs can provide products with the diversity needed for the discovery of new lead compounds or lead optimization employing combinatorial chemistry techniques. The search and discovery for new MCRs on one hand [5], and the full exploitation of already known multicomponent reactions on the other hand, are therefore of considerable current interest. In 1893, Pietro Biginelli has reported on the acid-catalyzed cyclo- condensation reaction of ethylacetoacetate, benzaldehyde and urea. The reaction was carried out by simply heating a mixture of the three components dissolved in ethanol with a catalytic amount of conc. HCl at reflux temperature. The product of this novel one- pot, three-component synthesis that precipitated on cooling the reaction mixture was identified correctly by Biginelli as dihy- dropyrimidin-2-one [6]. The scope of this reaction was gradually extended by the variation of all three building blocks, allowing access to a large number of multi-functionalized dihydropyr- imidines of medicinal use [3b,7e10]. Dihydropyrimidines show a diverse range of biological activities. They are known to possess activities such as antiviral (nitractin) [11], anticancer [12], anti- bacterial [13], analgesic and anti-inflammatory [13], as well as efficacy as calcium channel modulators and a1a-antagonists [14]. Thus development of methodologies for efficient lead structure identification and for pharmacophore variation of dihydropyr- imidines motif has always attracted the attention of pharmaceu- tical industry [15]. Furthermore, certain compounds bearing 1,3- dihydro-2H-indol-2-ones nucleus is used as a versatile lead mole- cule for designing potential antivirals [16], antituberculars [17], anticonvulsants [18] and anti-tumor therapeutic activities [19]. While, Schiff bases of 1,3-dihydro-2H-indol-2-ones and its deriva- tives were reported for antibacterial [20], antifungal [20], anti-HIV [21], anticonvulsant activities [22] and GAL3 receptor antagonists [23]. Prompted by the biological properties of dihydropyrimidines and 1,3-dihydro-2H-indol-2-ones nucleus, they were incorporated with thiadiazoles [24] and schiff bases were synthesized. Moreover, in the design of new drugs, the development of hybrid molecules through the combination of different pharmacophores in one frame may lead to compounds with interesting dual biological profiles, which is being reflected in present work. * Corresponding author. Tel.: þ91 2692 231894, þ91 2692 645801, þ91 9427946892; fax: þ91 2692 229189. E-mail address: drjpraval@yahoo.co.in (J.P. Raval). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.09.023 European Journal of Medicinal Chemistry 46 (2011) 5573e5579