Design, synthesis, in silico ADMET, docking, and antiproliferative evaluations of [1,2,4]triazolo[4,3‐c]quinazolines as classical DNA intercalators

Abstract

Eleven novel [1,2,4]triazolo [4,3-c]quinazolines were designed, synthesized, and evaluated against HepG2 and HCT-116 cells. The molecular design was performed to investigate the binding mode of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling. HCT-116 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compounds 6 f and 6 e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC 50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 µM, respectively. Although compounds 6 f and 6 e displayed less activity than doxorubicin (IC 50 = 7.94 ± 0.6 and 8.07 ± 0.8 µM, respectively), both could be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. The most active derivatives 6 a , 6 c , 6 e , and 6 f were evaluated for their DNA-binding activities. Compound 6 f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC 50 value (54.08 µM). Compounds 6 a , 6 c , and 6 e exhibited good DNA-binding affinities, with IC 50 values of 79.35, 84.08, and 59.35 µM, respectively. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles were calculated for the four most active compounds in comparison to doxorubicin as a reference drug. Our derivatives 6 a , 6 c , 6 e , and 6 f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6 a , 6 c , 6 e , and 6 f do not violate any rule.

Design, Molecular Docking, Synthesis, Anticancer and Anti-Hyperglycemic Assessments of Thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists

“…In continuance of our earlier works in the scope of the design and syntheses of novel anticancer medicines [36][37][38][39][40][41][42][43][44], particularly VEGFR-2 inhibitors [45][46][47][48][49][50][51][52][53][54], thiazolidine-2,4-diones bearing sulfonylthiourea moieties were synthesized to obtain the four keys of VEGFR-2 inhibitors pharmacophoric features (Figure 3) [55][56][57]. The focus of the current study was to utilize the lead modification approach for sorafenib, a potent VEGFR-2 inhibitor, to obtain novel potent inhibitors.…”

New [1,2,4]triazolo[4,3‐c]quinazoline derivatives as vascular endothelial growth factor receptor‐2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

“…to the docking algorithm's capability to obtain the reported binding mode of sorafenib via binding with Cys917 in the hinge region and Glu883 and Asp1044 in the DFG-binding domain (Figure 8). [46,54] The docking results demonstrated that the synthesized compounds were able to detect the VEGFR-2 kinase ATP binding site and interact with the critical amino acids in the same way that sorafenib does. The binding free energies are summarized in Table 6.…”

“…For the synthesis of the target compounds, the reactions sequence is illustrated in Schemes 1 and 2. According to the literature, [45,46] the commercially available 2-aminobenzoic acid 1 was fused with urea 2 at 200°C for 6 h to get quinazoline-2,4-dione 3. Chlorination of compound 3 was proceeded using phosphorous oxychloride and TEA to afford 2,4dichloroquinazoline 4.…”

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations

“…Depending on the mentioned facts, and the extension of producing new anti-cancers 30–36 , especially that intercalators for DNA 21–24 , 37–40 , it was reported herein modifications of EAPB0203 through hybridisation with privileged heterocyclic fragments as potent anticancer agents against MCF-7, HepG2 and HCT-116. Inhibition of DNA topoisomerase II, induction of apoptosis, cell cycle arrest, and inhibition of cancer cell proliferation are the main hallmarks applied to estimate potent chemotherapies for their anticancer activities 41 .…”