Design, synthesis, and anticancer evaluation of N-sulfonylpiperidines as potential VEGFR-2 inhibitors, apoptotic inducers.

A new panel of N-sulfonylpiperidine derivatives has been designed and synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Anti-proliferative activities of the synthesized members were tested against colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and breast cancer (MCF-7) cell lines. Compounds 3a, 4, 8, and 9 showed the highest activities against the tested cell lines. In particular, compound 8 showed excellent activities against HCT-116, HepG-2, and MCF-7 with IC50 values of 3.94, 3.76, and 4.43 µM, respectively. Such IC50 values are comparable to vinblastine (IC50 = 3.21, 7.35, 5.83 µM, respectively) and doxorubicin (IC50 = 6.74, 7.52, 8.19 µM, respectively). In vitro VEGFR-2 inhibitory activity of the most promising molecules (3a, 4, 8, and 9) indicated that compound 8 is the highest VEGFR-2 inhibitor with an IC50 of 0.0554 µM, compared to sorafenib (IC50 = 0.0416 µM). The most promising candidates (3a, 4, 8, and 9) were subjected to flow cytometry analyses to assess their effects on the cell cycle behavior and the apoptotic power against the three tested cell lines (HCT-116, HepG-2, and MCF-7). The tested compound arrested the tumor cells at both the G2/M and Pre-G1 phases. In addition, compound 9 was proved as the most effective apoptotic inducer among the tested compounds against the tested cells. Molecular docking studies against VEGFR-2 (PDB ID: 2OH4) revealed good binding modes of the synthesized compound similar to that of sorafenib. Computational investigation of ADMET parameters revealed the drug-likeness of the synthesized compounds.

Chemistry and Pharmacology of Delta-8-Tetrahydrocannabinol.

Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern hemisphere, its use has moved and flourished in the Western nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component in cannabis, with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ9-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ8-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ8-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ9-THC. The passing of the U.S. Farm Bill in 2018 led to an increase in the sale of Δ8-THC in the United States. The marketed products contain Δ8-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ8-THC will be presented. The issue of whether Δ8-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ8-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents, as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ8-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ9-THC, will be reviewed.

New apoptotic anti-triple-negative breast cancer theobromine derivative inhibiting EGFRWT and EGFRT790M: in silico and in vitro evaluation.

A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural characteristics to interact with EGFR's pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (T-1-DOMPA). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of T-1-DOMPA. Then, T-1-DOMPA's anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies, T-1-DOMPA bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of T-1-DOMPA were computed before preparation, and its drug-likeness was anticipated. Therefore, T-1-DOMPA was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of T-1-DOMPA against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC50 value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly, T-1-DOMPA inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC50 values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally, T-1-DOMPA prevented effectively the MDA-MB-231cell line's healing and migration abilities. Also, T-1-DOMPA's abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally, T-1-DOMPA caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell.

Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors.

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

A novel thieno[2,3-d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor-2: A story of computer-aided drug discovery.

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, a novel thieno[2,3-d]pyrimidine derivative has been designed and its activity against VEGFR-2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer-induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug-like nature of the designed candidate. According to the previous results, the thieno[2,3-d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR-2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI-38). Finally, the thieno[2,3-d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3-d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase-3, caspase-9, Bcl-2 associated X-protein, and B-cell lymphoma 2.

Computer-assisted drug discovery (CADD) of an anti-cancer derivative of the theobromine alkaloid inhibiting VEGFR-2.

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA's oral treatment didn't show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.

Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and in vivo studies.

This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC50 values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound 9d was the most potent member. It inhibited Topo II enzyme at IC50 value of 7.02 ± 0.54 µM with DNA intercalating IC50 of 26.19 ± 1.14 µM. Compound 9d was then subjected to an in vivo antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations.

Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers.

A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1-15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1, 9-12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.

Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies.

A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high in silico affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to in vitro cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound D-1 showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds A-1, C-6, and D-1 showed good IC50 values against VEGFR-2. Compound D-1 markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound D-1 caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound D-1 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies.

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC50 values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.

New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies.

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed by ELISA. Compounds 14o, 14l, and 14b showed the highest activities with VEGFR-2 protein concentrations of 586.3, 636.2, and 705.7 pg/ml, respectively. Additionally, the anti-angiogenic property of compound 14b against human umbilical vascular endothelial cell (HUVEC) was performed using a wound healing migration assay. Compound 14b reduced proliferation and migratory potential of HUVEC cells. Furthermore, compound 14b was subjected to further biological investigations including cell cycle and apoptosis analyses. Compound 14b arrested the HepG2 cell growth at the Pre-G1 phase and induced apoptosis by 16.52%, compared to 0.67% in the control (HepG2) cells. The effect of apoptosis was buttressed by a 4.8-fold increase in caspase-3 level compared to the control cells. Besides, different in silico docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.

Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies.

New nicotinamide derivatives 6, 7, 10, and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC50 values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC50 values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF-α by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 µM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M.

New 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFRWT). Compound 12b was the most potent member showing an IC50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFRT790M) (IC50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFRWT and EGFRT790M.

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation.

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (12d, 12f, 12i, 12l, and 13a) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l (IC50 = 10.50 µM and 15.21 µM against HepG2 and MCF-7, respectively) had the most promising VEGFR-2 inhibitory activity (IC50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.

New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies.

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.

Antiproliferative evaluations of triazoloquinazolines as classical DNA intercalators: Design, synthesis, ADMET profile, and molecular docking.

Novel triazoloquinazolines were designed and synthesized and evaluated as anticancer agents against HepG2 and HCT-116 cells. The biological testing data corresponded well to those of the molecular docking studies. The HCT-116 cell line was most affected due to the actions of our derivatives. Derivative 7a was the most potent one against both HepG2 and HCT116 cells, with IC50 = 7.98 and 5.57 µM, respectively. This compound showed anticancer activity that was nearly equipotent to that of doxorubicin against HepG2 cells, but higher than that of doxorubicin against HCT116 cells (IC50 = 7.94 and 8.07 µM, respectively). Compounds 8, 7b , and 6f showed excellent anticancer activities against both the HCT116 and HepG2 cell lines. The highly active compounds 6f , 7a , 7b , and 8 were evaluated for their DNA-binding activities. Compounds 7a and 8 showed the highest binding activities. These derivatives potently intercalate in DNA, at IC50 values of 42.90 and 48.13 µM, respectively. Derivatives 6f and 7b showed good DNA-binding activities, with IC50 values of 54.24 and 50.56 µM, respectively. Furthermore, in silico calculated ADMET profiles were established for our four highly active derivatives, in comparison to doxorubicin. Our derivatives 6f , 7a , 7b , and 8 showed a very good ADMET profile. Compounds 6f , 7a , 7b , and 8 follow Lipinski's rules, while doxorubicin violates three of these rules.

Triazoloquinazoline derived classical DNA intercalators: Design, synthesis, in silico ADME profile, docking, and antiproliferative evaluations.

Thirteen novel [1,2,4]triazolo[4,3-c]quinazoline derivatives as DNA intercalators were synthesized and their anticancer activities evaluated against HepG2 and HCT-116 cells. A docking study was carried out to explore how the new derivatives bind to active sites of DNA. The docking data were highly interrelated with that of biological testing. The HCT-116 cell line was the most sensitive one to the effect of the new derivatives. Compound 7c exhibited the highest anticancer activities against both the HepG2 and HCT116 cancer cell lines. Despite this compound displaying less activity than doxorubicin, it could be useful as a template for future manipulation, optimization, and investigation to produce other analogs with potential activity. The most active derivatives, 7c , 7b , and 7a were evaluated as DNA binders. Compound 7c displayed the highest binding affinity. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was calculated for the four most active compounds in comparison to doxorubicin as reference drug. Our derivatives 7a , 7b , and 7c displayed a very good calculated ADMET profile in comparison to doxorubicin.

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

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 6f and 6e were found to be the most potent derivatives over all the tested compounds against the two HepG2 and HCT116 cancer cell lines, with IC50 = 23.44 ± 2.9, 12.63 ± 1.2, and 25.80 ± 2.1, and 14.32 ± 1.5 µM, respectively. Although compounds 6f and 6e displayed less activity than doxorubicin (IC50 = 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 6a , 6c , 6e , and 6f were evaluated for their DNA-binding activities. Compound 6f displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (54.08 µM). Compounds 6a , 6c , and 6e exhibited good DNA-binding affinities, with IC50 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 6a , 6c , 6e , and 6f displayed very good in-silico-predicted ADMET profiles. Doxorubicin violates three of Lipinski's rules, our derivatives 6a , 6c , 6e , and 6f do not violate any rule.