Mechanochemical Synthesis and Molecular Docking Studies of New Azines Bearing Indole as Anticancer Agents

Abstract

The development of new approaches for the synthesis of new bioactive heterocyclic derivatives is of the utmost importance for pharmaceutical industry. In this regard, the present study reports the green synthesis of new benzaldazine and ketazine derivatives via the condensation of various carbonyl compounds (aldehydes and ketones with the 3-(1-hydrazineylideneethyl)-1H-indole using the grinding method with one drop of acetic acid). Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. Furthermore, the anticancer activities of the reported azine derivatives were evaluated against colon, hepatocellular, and breast carcinoma cell lines using the MTT technique with doxorubicin as a reference medication. The findings suggested that the synthesized derivatives exhibited potential anti-tumor activities toward different cell lines. For example, 3c, 3d, 3h, 9, and 13 exhibited interesting activity with an IC50 value of 4.27–8.15 µM towards the HCT-116 cell line as compared to doxorubicin (IC50 = 5.23 ± 0.29 µM). In addition, 3c, 3d, 3h, 9, 11, and 13 showed excellent cytotoxic activities (IC50 = 4.09–9.05 µM) towards the HePG-2 cell line compared to doxorubicin (IC50 = 4.50 ± 0.20 µM), and 3d, 3h, 9, and 13 demonstrated high potency (IC50 = 6.19–8.39 µM) towards the breast cell line (MCF-7) as compared to the reference drug (IC50 = 4.17 ± 0.20 µM). The molecular interactions between derivatives 3a-h, 7, 9, 11, 13, and the CDK-5 enzyme (PDB ID: 3IG7) were studied further using molecular docking indicating a high level of support for the experimental results. Furthermore, the drug-likeness analysis of the reported derivatives indicated that derivative 9 (binding affinity = −8.34 kcal/mol) would have a better pharmacokinetics, drug-likeness, and oral bioavailability as compared to doxorubicin (−7.04 kcal/mol). These results along with the structure–activity relationship (SAR) of the reported derivatives will pave the way for the design of additional azines bearing indole with potential anticancer activities.

Synthesis, Biological Evaluation, and Molecular Docking of Novel Azolylhydrazonothiazoles as Potential Anticancer Agents

“…Recently, the utility of thiazolylhyrazono-thiazoles has been endorsed as potential anticancer drugs. − In addition, azolylthiazoles have been handled in several clinically available anticancer drugs, such as ixabepilone, dabrafenib and dasatinib (Figure ). Otherwise, the conjugated hydrazone system has been widely employed in pharmacological research as antitumor , agents (Figure ). The integration of a single species of two or more pharmacophores is a useful structural modification method known as molecular hybridization.…”

“…Based on the examples described above, and in continuation of our attempts to synthesize heterocycles with anticancer activity. − ,,− We aimed in this study to prepare a hybrid structural scaffold of thiazolylthiazoles, with hydrazone linker, and investigate their potential activities as therapeutic agents for cancer therapy. The molecular docking study of the isolated products into epidermal growth factor receptor tyrosine kinase domain (EGFR TK) binding site was also demonstrated to predict the binding affinity and determine the interactions of the proposed derivatives 7a–e , 9a–f and 11a,b (Figure ).…”

Discovery of 3-Formyl-N-(un)Substituted Benzylindole Pyrimidines as an Acaricidal Agent and Their Mechanism of Action

“…15 It also occurs in the oil of jasmine, cloves, and coal tar. 16 Indole and its derivatives possess diverse biological properties including anticancer, 17 antioxidant, 18,19 anti-inflammatory, 20 and pesticidal activities. 21−24 On the other hand, it is worth noting that the pyrimidine heterocycle as the most common diazine showed some important agricultural biological activities, including antifungal (A, Figure 1), 25 insecticidal (B, Figure 1), 26 antiviral (C, Figure 1), 27 and antibacterial (D, Figure 1) effects.…”

“…It also occurs in the oil of jasmine, cloves, and coal tar . Indole and its derivatives possess diverse biological properties including anticancer, antioxidant, , anti-inflammatory, and pesticidal activities. − On the other hand, it is worth noting that the pyrimidine heterocycle as the most common diazine showed some important agricultural biological activities, including antifungal (A, Figure ), insecticidal (B, Figure ), antiviral (C, Figure ), and antibacterial (D, Figure ) effects . To find the potent acaricide candidate, consequently, in this study, we wanted to prepare a series of 3-formyl- N -(un)­substituted benzylindole pyrimidines (Figure ) by introduction of the pyrimidine fragment into the indole skeleton through the successive Vilsmeier–Haack–Arnold (VHA), aldol condensation, and cyclization reactions.…”

Synthesis and Evaluation of Novel Metacetamol Derivatives with Hydrazone Moiety as Anticancer and Antimicrobial Agents

“…[8][9][10][11][12] Additionally, hydrazone derivatives have represented promising anticancer activity by inhibiting cancer cell proliferation and inducing apoptosis. [13][14][15][16][17][18][19] The mechanism of action of these compounds involves targeting specific cellular pathways and enzymes, facilitated by their multiple hydrogen bond acceptor/donor atoms that can interact with biological targets. Importantly, this functional group is found in several commercially available drugs used to treat diverse diseases including cancer, fungal and bacterial infections (Figure 1).…”