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- Title
Alkylated Indole Hybrids: Synthesis and RTU Formulation Development for Treatment of Cancer.
- Authors
Thomas, Asha; More, Ghansham; Jadhav, Pranali; Chitlange, Sohan
- Abstract
Introduction: Indole heterocyclic compounds have shown diverse biological activities, making them privileged scaffold for drug development. In this study, we focused on design, synthesis and formulation of hybrid indole compounds containing 2-chloro-N-(2-chloroethyl)-N-methylethanamine as promising anti-cancer agents. Methods: In-silico study was conducted, wherein a library of 1500 indole compounds were designed, screened based on electrostatic properties and shape similarities using TorchLite 10.5.0. The eXtened Electron Distribution (XED) pattern was studied and compared with reference listed drugs (RLDs). The binding affinity of designed ligands to DNA target (PDB ID: 1AXL), was studied using Glide program. Multivariate analysis, ECFP-6 fingerprints and scatter plots were used which demonstrated closeness of designed compounds with RLDs. Alkylated indole derivatives were synthesized from substituted indoles with oxalyl chloride and replacement of chloride using diethanolamine, with further chlorination using thionyl chloride. The compounds were effectively characterized using physicochemical properties and spectral analysis. In vitro MTT assay was performed to evaluate anti-cancer potential of synthesized compounds. Stable and cost-effective Ready To Use (RTU) formulation of AGSPBM1006 indole alkylating agent was developed using 95% dehydrated alcohol as vehicle. The stability testing (accelerated condition: 40°C/75%RH) and assay of related substances present in formulation were studied using validated RP-HPLC method. Results: In the in-silico study, designed compound AGSPBM1006 showed lowest binding energy (-9.130) when compared to Bendamustine RLD (-6.232) and is capable of binding with minor grove in the active site. The compound demonstrated comparable IC50 values (2.20 and 3.97) to RLD bendamustine (2.31 and 4.35) against HEPG2 and MCF-7 cell lines respectively. Furthermore, stable RTU formulation of AGSPBM1006 was formulated using QbD approach with critical process parameters optimized through DoE. Conclusion: The alkylated Indole hybrid compound AGSPBM1006 identified through rigorous in-silico studies with promising anti-cancer potential can serve as a lead for further investigations for development of novel anti-cancer agents.
- Subjects
INDOLE compounds; ALKYLATING agents; OXALYL chloride; ELECTRON distribution; CARCINOGENESIS; INDOLE
- Publication
Malaysian Journal of Medicine & Health Sciences, 2024, Vol 20, p8
- ISSN
1675-8544
- Publication type
Abstract