Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

Abstract

C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC 50 = 0.67-4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery.C-Glycosides are stable surrogates of O-glycosides and are often used as investigative tool in chemical biology and medicinal chemistry, in particular C-glycoside analogues are often used as substrate mimics for different enzymes involved in the carbohydrate metabolism 1-10 . The use of glycomimetic in the design of inhibitors has proven to be a successful approach and now constitutes one of the most attractive ways to develop new generations of effective and selective inhibitors 11 . α, β-unsaturated ketone is a central core for many significant biological compounds 12,13 . According to literature α, β-unsaturated ketone derivatives from natural and synthetic analogues exhibit diverse pharmacological activities such as anti-tuberculosis, anti-inflammatory, anticancer, antineoplastic, antibacterial, antifungal, antimalarial, antiviral, antiallergic, estrogenic 12 and COX-2 inhibitor 13 .Pyrazoline derivatives are important biologically active heterocyclic compounds. These derivatives are the subject of many research studies due to their widespread potential biological activities such as anticancer, antioxidant, antibacterial activities 14 and COX-2 inhibitor 15 . The most prominent compounds containing pyrazoline nucleus are ampyrone, phenazone and propyphenzone. Isoxazole heterocycle is well known for its medicinal relevance 16,17 . There are isoxazole nucleus containing drug molecules currently available in market, such as acetylsulfisoxazole, cycloserine, sulfisoxazole, and zonisamide etc. These drugs possess antimicrobial 18 , antioxidant 19,20 tuberculostatic 21 neurotoxic 22 , antiepileptic activities 23,24 and COX-2 inhibitor 25 . The comparable activities are also observed in other isoxazole derivatives, captivates researcher to search for newer bioactive compounds of using this as pharmacophore. α, β-...

Pyrazoline Hybrids as Promising Anticancer Agents: An Up-to-Date Overview

“…Pyrazoline-bridged indole C-glycoside 36 ( Figure 13 ) displayed low micromolar and selective cytotoxicity against MCF-7 (IC 5 0 = 4.67 μM) compared to other breast cancer cell lines [ 92 ]. As a matter of fact, 36 was less active against MDA-MB-231 (IC 50 = 35.5 μM) and far less active against MDA-MB-453 (IC 50 not determined—cell viability was determined at 69.6% at 25 μM).…”

New Pyrazoline Derivatives Containing Imine Moiety: Synthesis, Characterization and Antimicrobial Study

“…Chalcone derivative 1 was prepared by the reaction of 4-aminoacetophenone with 4pyridinecarboxaldehyde in ethanol, in a presence of sodium hydroxide 40% solution according to Claisen-Schmidt condensation, while the pyrazoline compound (2) was obtained by the reaction of chalcone compound (1) with hydrazine hydrate 80% in ethanol. Schiff's bases (3)(4)(5)(6)(7)(8) were synthesized from the reaction of compound 2 with different aromatic aldehydes in acidic ethanolic solution, while the pyrazoline derivatives (9 and 10) were prepared by the reaction pyrazoline derivative (2) with the corresponding anhydride (maleic or phthalic anhydride) in glacial acetic acid in a presence of anhydrous sodium acetate (Scheme 1). The structures of obtained compounds were confirmed by spectral analysis (see experimental section).…”

“…The development of heterocyclic chemistry is very rapid, especially in the development of synthetic methods and the biological activity of synthetic materials [3]. Pyrazoline has been widely incorporated into the structure of many important medical and biochemical reagents that have been effectively utilized as anti-bacterial [4], anti-inflammatory [5], anti-viral [6], anti-fungal [7], anti-cancer [8], analgesic and insecticidal agents [9]. In the last few years, a significant and important portion of research in the field of heterocyclic chemistry has been dedicated to pyrazolines and their derivatives, especially those linked by various functional groups such as imine group (Schiff's-Base).…”

“…Therefore, great importance appeared in studying the biological effects of these kinds of derivatives due to their activity against several pathogenic bacteria and fungi [10], this encouraged us to synthesize a new series of pyrazoline derivatives. The synthesized compounds (3)(4)(5)(6)(7)(8)(9)(10) were screened against some bacterial species (gram positive and gram negative) and fungal against (Candida albicans) and the screened results showed moderate to high efficacy.…”

“Azole” as privileged heterocycle for targeting the inducible cyclooxygenase enzyme

“…Glycosides appended to isoxazoles in the hybrid compounds 109 (Figure 18) mainly deliberated as anticancer agents displayed marked inhibition of COX‐2 enzyme, superior than the commercial drug celecoxib. Molecular docking analysis on test compounds in the active site of COX‐2 isoenzyme revealed hydrogen bonding interactions and hydrophobic interactions between the carbohydrate moiety and the active site residues (Kumari et al, 2020). Isoxazole based scaffolds 110–111a–b (Figure 18) validated the selective COX‐2 inhibition profile of isoxazole nucleus by displaying potent activities in submicromolar range.…”