1. Academic Validation
  2. Ultrasound assisted one-pot synthesis of rosuvastatin based novel azaindole derivatives via coupling-cyclization strategy under Pd/Cu-catalysis: Their evaluation as potential cytotoxic agents

Ultrasound assisted one-pot synthesis of rosuvastatin based novel azaindole derivatives via coupling-cyclization strategy under Pd/Cu-catalysis: Their evaluation as potential cytotoxic agents

  • Bioorg Chem. 2022 Jul;124:105857. doi: 10.1016/j.bioorg.2022.105857.
Jetta Sandeep Kumar 1 Gangireddy Sujeevan Reddy 1 Raghavender Medishetti 1 Kazi Amirul Hossain 2 B Thirupataiah 1 Jhansi Edelli 2 Shilpak Dilip Bele 2 Rebecca Kristina Edwin 2 Alex Joseph 3 Gautham G Shenoy 3 C Mallikarjuna Rao 3 Manojit Pal 4
Affiliations

Affiliations

  • 1 Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576 104, Karnataka, India.
  • 2 Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
  • 3 Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576 104, Karnataka, India.
  • 4 Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India. Electronic address: manojitpal@rediffmail.com.
Abstract

Addressing the increasing incidences of Cancer worldwide along with the multifaceted problem of drug resistance via development of new Anticancer agents has become an essential goal. Due to the known cytotoxic effects and reported Akt inhibitory potential of azaindoles we designed a new framework incorporating the structural features of rosuvastatin and 5- or 7-azaindole. The framework was used to construct a library of small molecules for further pharmacological evaluation. The design was supported by the docking studies of two representative molecules in silico. A one-pot sonochemical approach was established for the synthesis of these rosuvastatin based azaindoles that involved the coupling-cyclization of a rosuvastatin derived terminal alkyne with appropriate 3-iodopyridine derivatives under Pd/Cu-catalysis. When tested using an MTT assay, some of the synthesized compounds showed desirable cytotoxic effects against three Cancer cell lines e.g. HCT 116, Hep G2 and PA-1 but no significant effects against the non-cancerous HEK cell line. According to the SAR the 5-azaindole ring appeared to be marginally better than the 7-azaindole whereas the activity was varied with the variation of sulfonamide moiety attached to the N-1 atom of the azaindole ring. Among all the groups present in the sulfonamide moiety the p-MeC6H4 group appeared to be most effective in terms of activity. While 3b and 5b were identified as initial hit molecules the compound 5b (in addition to 3b) also showed significant inhibition of Akt1 in vitro that was reflected by its strong interaction with Akt1 in silico (with the docking score -11.7 kcal/mol) involving two H-bonding interactions with Ser7 and Asp439 residues. Further, a reasonable ADME was predicted for 5bin silico. Being a potent inhibitor (MIA Paca-2 IC50 = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound.

Keywords

Azaindole; Cytotoxicity; In silico study; Pd-catalyst; Rosuvastatin.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146459
    99.74%, Akt1抑制剂
    Akt