Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties

Abstract

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand–protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from − 8.1394 to − 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.

Potential DPP IV Inhibitory Peptides from Dry-Cured Pork Loins after Hydrolysis: An In Vitro and In Silico Study

“…In drug development, the pharmacokinetic and pharmacodynamic properties of potential drug candidates are as important as their efficacy, specificity, and safety [35]. This is important because, in pharmacological terms, potential distributed metabolites will act directly on cellular systems, inactive metabolites may inactivate the administered compound and reduce its in vivo activity, and neutral metabolites will be automatically excreted from the kidneys [36]. Assessment of these specific properties, namely ADMET (absorption, distribution, metabolism, excretion, toxicity) for food peptides is therefore essential in their initial stage of identification as a biomolecule.…”

Studies Directed towards the Synthesis of the Acridone Family of Natural Products: Total Synthesis of Acronycines and Atalaphyllidines

“…21 Using the procedure GP-2, salicylic acid 9a (2.0 g, 14.49 mmol) and phloroglucinol 6 (1.82 mg, 14.49 mmol) were used to provide compound 10a (2.77 g, 84%) as a reddish brown solid. 1 H NMR (400 MHz, ): 12.87 (1H, s br ), 11.12 (1H, s br ), 8.14 (1H, d, J = 8.1 Hz), 7.86 (1H, t, J = 7.9 Hz), 7.60 (1H,d,J = 8.5 Hz),7.47 (1H,t,J = 7.4 Hz),6.41 (1H,s),6.22 (1H,s); 13 C (100 MHz, DMSO-d 6 ): 179. 7,165.9,162.8,157.4,155.3,135.6,125.2,124.4,119.8,117.7,102.2,98.1,94.0;HRMS (ESI) (100 MHz,166.6,163.9,140.0,136.3,133.2,128.4,127.3,126.7,125.8,107.5,103.0,101.0 acridin-7(12H)one (2a).…”

“…: 216−218 °C; 1 H NMR (400 MHz, DMSO-d 6 ): 14. 65 (1H,s),11.15 (1H,s),8.16 (1H,d,J = 8.7 Hz),m),m), 7.00 (1H, d, J = 9.9 Hz), 6.04 (1H, s), 5.73 (1H, d, J = 10.0 Hz), 1.43 (6H, s); 13 C (100 MHz, DMSO-d 6 ): 180. 5, 163.8, 159.2, 140.8, 137.7, 133.9, 125.7, 124.8, 121.8, 118.8, 117.5, 116.0, 103.9, 98.0, 96.2, 77.0, 27.4 5,163.3,159.1,147.3,136.8,131.2,125.6,121.7,119.5,115.9,115.8,113.2,104.1,98.3,96.5,77.1,56.3,27.4HRMS (ESI) xanthen-7(3H)-one (11a).…”

“…: 234−236 °C; 1 H NMR (400 MHz, CDCl 3 ): 14.71 (1H, s), 8.55 (1H, d, J = 8.0 Hz), 7.61 (1H, t, J = 8.1 Hz), 7.55 (1H, d, J = 7.9 Hz), 7.47 (1H, t, J = 8.1 Hz), 6.63 (1H, d, J = 10.0 Hz), 6.39 (1H, s), 5.70 (1H, d, J = 10.0 Hz), 1.43 (6H, s); 13 C (100 MHz, CDCl 3 ): 132. 6,129.3,128.4,128.2,126.3,125.5,116.0,103.4,78.3,28.6;HRMS (ESI) ,dd,J = 1.9,6.3 Hz),m),7.54 (1H,d,J = 8.2 Hz),7.26 (1H,t,J = 7.6 Hz),6.68 (1H,d,J = 9.5 Hz),6.38 (1H,s),5.61 (1H,d,J = 10.1 Hz), 3.83 (3H, s), 3.79 (3H, s), 1.49 (6H, s); 13 C (100 MHz, DMSO-d 6 ): 175.3, 162.1, 158.6, 146.1, 144.1, 132.7, 125.8, 124.6, 123.0, 121.5, 117.0, 109.6, 102.7, 94.1, 76.2, 55.9, 43.9,…”

Synthetic route towards 1,2,3,4-tetrahydroquinoxaline/piperidine combined tricyclic ring system

“…5 Both quinoxalines and their derivatives 1,2,3,4-tetrahydroquinoxalines represent an important class of nitrogen-containing heterocycles that can be found in many pharmacologically active natural and synthetic compounds (Figure 1). 6,7 1,2,3,4-tetrahydroquinoxalines are structural motifs present in compounds that act as anticancer agents, 8 prostaglandin D2 receptor antagonists, 9 cholesteryl ester transfer protein inhibitors, 10 and others. [11][12][13] Many synthetic procedures for the synthesis of functionalized 1,2,3,4-tetrahydroquinoxalines have been reported so far.…”