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  3. New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis

New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis

  • Bioorg Med Chem Lett. 2021 Jul 15:44:128094. doi: 10.1016/j.bmcl.2021.128094.
Irfan Khan 1,  Thipparapu Ganapathi 2,  Md Muzaffar-Ur- Rehman 3,  Mohd Adil Shareef 4,  C Ganesh Kumar 5,  Ahmed Kamal 6
Affiliations

Affiliations

  • 1 Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India. Electronic address: irfankhanacs@gmail.com.
  • 2 Stem Cell Research Division, National Institute of Nutrition (NIN), Indian Council of Medical Research (ICMR), Hyderabad 500007, Telangana, India. Electronic address: ganapathi.usa@gmail.com.
  • 3 Catalysis and Fine Chemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India. Electronic address: m.muzaffar687@gmail.com.
  • 4 Academy of Scientific and Innovative Research, Ghaziabad 201002, India; Centre for Fluoro-Agrochemicals, CSIR-Indian Institute of Chemical Technology, Tarnaka 500007, Hyderabad, India. Electronic address: adilshareef07@gmail.com.
  • 5 Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India.
  • 6 Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad 201002, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India. Electronic address: ahmedkamal@iict.res.in.
PMID: 33964437 DOI: 10.1016/j.bmcl.2021.128094
Abstract

To continue the quest of newer Anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different Cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic Cancer cells) with IC50 value 7.4 μM and 4.3 μM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC50 = 4.2 μM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate Apoptosis by activating Caspase 3 and 9 Enzymes which was confirmed by Annexin-FITC assay and Caspase assay. Moreover, docking study suggested their binding modes and interactions with Caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q2 = 0.631, r2 = 0.977) and CoMSIA (q2 = 0.686, r2 = 0.954) on PANC-1 Cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced Anticancer activity.

Keywords

3D-QSAR; Anti-pancreatic; Anti-proliferative; Apoptosis; Indenopyrazole; Oxadiazole.

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