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Design, synthesis, and evaluation of 4-(substituted)phenyl-2-thioxo-3,4-dihydro-1H-chromino[4,3-d]pyrimidin-5-one and 4-(substituted)phenyl-3,4-dihydro-1H-chromino[4,3-d]pyrimidine-2,5-dione analogs as antitubercular agents

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Abstract

This paper focuses on the design and antitubercular activity of molecules which are a hybrid of coumarin and pyrimidine nuclei. A set of 16 compounds, viz. 4-(substituted)phenyl-3,4-dihydro-1H-chromino[4,3-d]pyrimidine-2,5-diones and 4-(substituted)phenyl-2-thioxo-3,4-dihydro-1H-chromino[4,3-d]pyrimidin-5-ones have been synthesized using green chemistry principles and evaluated for antitubercular activity by microplate Alamar blue assay (MABA) and luminescence-based low oxygen-recovery assay (LORA) with rifampicin as the standard. The required Mycobacterium tuberculosis H37Rv strain for LORA was cultured using a plasmid bearing an acetamidase promoter driving a bacterial luciferase gene for signal enhancement and were allowed to adapt to low oxygen content in the fermenter. Compounds 5d, 5e, and 5g demonstrated maximum antitubercular activity, with % inhibition values of 58, 55, and 45 based on MABA and 62, 35 and 37 based on the LORA tests at 128 μM. To understand the relationship between structure and activity, recursive partitioning (RP) models were developed. Two different RP models were built, one based on the antitubercular activity and the other based on the toxicity of the molecules. The decision tree could identify descriptors that discriminate the active and inactive as well as toxic and less toxic 3,4-annelated coumarin analogs. This RP model will be utilized in further work to design more potent molecules.

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Acknowledgments

The computational, synthetic, and evaluation studies were possible due to the grants received from the All India Council for Technical Education (F. nos. 8022/RID/NPROJ/RPS-5/2003-04 and 8023/BOR/RID/RPS-181/2008-09), Department of Biotechnology (File no. BT/PR11810/BRB/10/690/2009), Council for Scientific Research (File no. 01/2399/10/EMRII) New Delhi and University of Mumbai (F. no. APD/237/157/2010).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Mumbai, 400 098, India

    Premlata K. Ambre, Raghuvir R. S. Pissurlenkar, Ravindra D. Wavhale, Mushtaque S. Shaikh, Vijay M. Khedkar & Evans C. Coutinho

  2. Tuberculosis Research Centre, University of Illinois, Chicago, IL, USA

    Baojie Wan & Scott G. Franzblau

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  1. Premlata K. Ambre
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  2. Raghuvir R. S. Pissurlenkar
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  3. Ravindra D. Wavhale
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  4. Mushtaque S. Shaikh
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  5. Vijay M. Khedkar
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  6. Baojie Wan
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  7. Scott G. Franzblau
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  8. Evans C. Coutinho
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Correspondence to Evans C. Coutinho.

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Ambre, P.K., Pissurlenkar, R.R.S., Wavhale, R.D. et al. Design, synthesis, and evaluation of 4-(substituted)phenyl-2-thioxo-3,4-dihydro-1H-chromino[4,3-d]pyrimidin-5-one and 4-(substituted)phenyl-3,4-dihydro-1H-chromino[4,3-d]pyrimidine-2,5-dione analogs as antitubercular agents. Med Chem Res 23, 2564–2575 (2014). https://doi.org/10.1007/s00044-013-0850-7

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