Natural-Product-Inspired Microwave-Assisted Synthesis of Novel Spirooxindoles as Antileishmanial Agents: Synthesis, Stereochemical Assignment, Bioevaluation, SAR, and Molecular Docking Studies
Nawal Kishore Sahu,
Ritu Sharma,
Kshirsagar Prasad Suhas,
Jyoti Joshi,
Kunal Prakash,
Richa Sharma,
Ramendra Pratap,
Xiwen Hu,
Sukhbir Kaur,
Mukesh Jain,
Carmine Coluccini,
Paolo Coghi,
Sandeep Chaudhary
Affiliations
Nawal Kishore Sahu
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India
Ritu Sharma
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India
Kshirsagar Prasad Suhas
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow 226002, India
Jyoti Joshi
Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh 160014, India
Kunal Prakash
Department of Chemistry, University of Delhi, North Campus, Delhi 110007, India
Richa Sharma
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India
Ramendra Pratap
Department of Chemistry, University of Delhi, North Campus, Delhi 110007, India
Xiwen Hu
School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
Sukhbir Kaur
Parasitology Laboratory, Department of Zoology, Panjab University, Chandigarh 160014, India
Mukesh Jain
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India
Carmine Coluccini
Institute of New Drug Development, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan
Paolo Coghi
School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
Sandeep Chaudhary
Laboratory of Organic and Medicinal Chemistry (OMC Lab), Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur 302017, India
Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2′-pyrrolidin]-2-one/spiro[indoline-3,3′-pyrrolizin]-2-one 23a–f, 24a–f, and 25a–g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a–h, various substituted chalcones 21a–f, and 22a–c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a, 24e, 24f, and 25d were found to be the most active compounds of the series and showed IC50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a, 24e, 24f, and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.
