Rational design and synthesis of novel quinazolinone N-acetohydrazides as type II multi-kinase inhibitors and potential anticancer agents.

In the current investigation, a new class of quinazolinone N-acetohydrazides 9a-v was designed as type II multi-kinase inhibitors. The target quinazolinones were tailored so that the quinazolinone moiety would occupy the front pocket of the binding sites of VEGFR-2, FGFR-1 and BRAF kinases, meanwhile, the phenyl group at position 2 would act as a spacer which was functionalized at position 4 with an N-acetohydrazide linker that could achieve the key interactions with the essential gate area amino acids. The hydrazide moiety was linked to diverse aryl derivatives to occupy the hydrophobic back pocket of the DFG-out conformation of target kinases. The synthesized quinazolinone derivatives 9a-v demonstrated moderate to potent VEGFR-2 inhibitory activity with IC50 spanning from 0.29 to 5.17 µM. Further evaluation of the most potent derivatives on FGFR-1, BRAFWT and BRAFV600E showed that the quinazolinone N-acetohydrazides 9d, 9e, 9f, 9l and 9m have a potent multi-kinase inhibitory activity. Concurrently, 9b, 9d, 9e, 9k, 9l, 9o, 9q demonstrated potent growth inhibitory activity on NCI cancer cell lines with GI50 reaching 0.72 µM. In addition, compound 9e arrested the cell cycle progression in MDA-MB-231 cell line at the G2/M phase and showed the ability to induce apoptosis.

New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies.

Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog 3 as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC50 values in the nanomolar range, compounds 8a, 5 were the most promising suppressors, producing IC50 values of 2.31 and 3.05 nM compared to Olaparib with IC50 of 4.40 nM. Compounds 4, 10b, and 11b showed a mild decrease in the potency of the IC50 range of 6.35-8.73 nM. Furthermore, compounds 4, 5, 8a, 10b, and 11b were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound 5 exhibited the most significant potency of IC50; 2.57 µM, whereas the IC50 value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound 5, which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds 4, 5, 8a, 10b, and 11b into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound 5 could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.

New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies.

Motivated by the potential anticancer activity of both coumarin and 2-aminothiazole nuclei, a new set of thiazol-2-yl hydrazono-chromen-2-one analogs were efficiently synthesized aiming to obtain novel hybrids with potential cytotoxic activity. MTT assay investigated the significant potency of all the target compounds against the human cervical cancer cell lines (HeLa cells). Cell cycle analysis showed that the representative compound 8a led to cell cycle cessation at G0/G1 phase indicating that CDK2/E1complex could be the plausible biological target for these newly synthesized compounds. Thus, the most active compounds (7c and 8a-c) were tested for their CDK2 inhibitory activity. The biological results revealed their significant CDK2 inhibitory activity with IC50 range of 0.022-1.629 nM. Moreover, RT-PCR gene expression assay showed that compound 8a increased the levels of the nuclear CDK2 regulators P21 and P27 by 2.30 and 5.7 folds, respectively. ELISA tequnique showed also that compound 8a led to remarkable activation of caspases-9 and -3 inducing cell apoptosis. QSAR study showed that the charge distribution and molecular hydrophobicity are the structural features affecting cytotoxic activity in this series. Molecular docking study for the most potent cytotoxic compounds (7c and 8a-c) rationalized their superior CDK2 inhibitory activity through their hydrogen bonding and hydrophobic interactions with the key amino acids in the CDK2 binding site. Pharmacokinetic properties prediction of the most potent compounds showed that the newly synthesized compounds are not only with promising antitumor activity but also possess promising pharmacokinetic properties.

Rational design and synthesis of new tetralin-sulfonamide derivatives as potent anti-diabetics and DPP-4 inhibitors: 2D & 3D QSAR, in vivo radiolabeling and bio distribution studies.

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I-substrate in the pancreas and rapid clearance from most of the body organs.

Synthesis and molecular docking study of new benzofuran and furo[3,2-g]chromone-based cytotoxic agents against breast cancer and p38α MAP kinase inhibitors.

This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked various heterocyclic functionalities using concise synthetic approaches aiming to gain new antiproliferative candidates against MCF-7 breast cancer cells of p38α MAP kinase inhibiting activity. The biological data proved the significant sensitivity of breast cancer cell lines MCF-7 towards most of the prepared compounds in comparison with doxorubicin. In addition, compounds IIa,b, Va,b, VIa,b, VIIa,b, VIIIa,b, XIc showed significant in vitro p38α MAPK inhibiting potency comparable to the reference standard SB203580. Cell cycle analysis and apoptosis detection data demonstrated that compound VIa induced G2/M phase arrest and apoptosis in MCF-7 cancer cells, in addition to its activation of the caspases-9 and -3. Gold molecular docking studies rationalized the highly acceptable correlation between the calculated docking scores of fitness and the biological data of p38α MAP kinase inhibition. The newly prepared benzofuran and 5H-furo[3,2-g]chromone derivatives might be considered as new promising nuclei in anti-breast cancer chemotherapeutics for further functionalization, optimization and in-depth biological studies.

Synthesis and molecular docking studies of new furochromone derivatives as p38α MAPK inhibitors targeting human breast cancer MCF-7 cells.

Based on the reported high expression of p38α MAP kinase in invasive breast cancers and the activity of different functionalized chromone derivatives as p38α inhibitors, a new set of 4,9-dimethoxy/4-methoxy-7-methyl-5-oxo-5H-furo[3,2-g]chromone derivatives were efficiently synthesized aiming to introduce new p38α MAP kinase suppressors as new anti-breast cancer tools. Using GOLD program, molecular docking study of the target compounds into p38α MAP kinase binding pocket was performed to highlight their scores, mode of binding and the important interactions to the amino acid residues of the enzyme. MTT assay investigated that fifteen target compounds produced marked cytotoxic potency higher than that obtained by Doxorubicin against MCF-7 cancer cells of IC50 values ranging from 0.007 to 0.17µM vs IC50; 0.62µM of doxorubicin. Eleven selected compounds were evaluated for their inhibitory potency against p38α MAPK kinase. The derivatives IVa, Va,b, VIa, IXb and XIIIa represented significant activity (IC50; 0.19-0.67µM) comparing to the reference drug SB203580 (IC50; 0.50µM). In virtue of its promising cytotoxic and p38α MAP kinase inhibition potency, the furochromone derivative IXb was selected as a representative example to investigate its mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cell lines. The results showed that the compound IXb induced cell cycle cessation at G2/M phase preventing its mitotic cycle, alongside its noteworthy activation of caspases-9 and -3 which might mediate the apoptosis of MCF-7 cells.

A novel class of substituted spiro [quinazoline-2,1'-cyclohexane] derivatives as effective PPAR-1 inhibitors: molecular modeling, synthesis, cytotoxic and enzyme assay evaluation.

Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.

Synthesis, cytotoxic evaluation and molecular docking study of novel quinazoline derivatives as PARP-1 inhibitors.

Novel series of spiro[(2H,3H)-quinazoline-2,1'-cyclohexane] derivatives (I-XVI) were synthesized and biologically evaluated as cytotoxic agents against human breast carcinoma cell lines (MCF-7) using doxorubicin as a reference drug. Most of the tested compounds displayed promising cytotoxic activity, especially derivatives V, VIb and XIb. The most active compounds were docked into the PARP-1 enzyme binding site to predict the ligand-protein binding modes. Lipinski rule of five and ADME profile suggested strongly that compounds V and VIb are promising agents as breast cancer inhibitors with drug likeness approach that have PARP-1 inhibitory activity. The structures of all newly synthesized compounds were confirmed by microanalysis and IR, 1H-NMR and mass spectral data.

Multi-functionalization of reduced graphene oxide nanosheets for tumor theragnosis: Synthesis, characterization, enzyme assay, in-silico study, radiolabeling and in vivo targeting evaluation.

BACKGROUND: In this study, a combination of nanotechnology, organic synthesis and radiochemistry were utilized in order to design an efficient nano-system conjugated with a suitable radionuclide and an antitumor agent for possible application as tumor theragnostic agent. METHOD: Four novel compounds (3 and 4a-c) bearing tetrahydroquinazoline-7-sulfonohydrazide or 1,2,3,4-tetrahydroquinazoline-7-sulfonamide scaffold were designed. Then, docking study predicted that the compounds can be considered as potential inhibitors for PARP-1. Following that; the four compounds were synthesized and properly characterized using 1HNMR, 13CNMR, IR and Mass spectroscopy. The cytotoxic effect of the four compounds was evaluated against breast cancer cell line (MDA-MB-436), where compound 3 showed the most promising cytotoxic effect. The inhibitory effect of the four compounds was evaluated in vitro against PARP-1. RESULT: Carboxylated graphene oxide nanosheets (NGO-COOH) were synthesized by a modified Hummer's method and has size of range 40 nm. The NGO-COOH nanosheets were proven to be safe and biocompatible when tested in vitro against normal human lung fibroblast cells (MRC-5). The prepared NGO-COOH nanosheets were conjugated with compound 3 then radiolabeled with 99mTc to yield 99mTc-NGO-COOH-3 with a radiochemical yield of 98.5.0 ± 0.5%. 99mTc-NGO-COOH-3 was injected intravenously in solid tumor bearing mice to study the degree of localization of the nano-system at tumor tissue. The results of the study revealed, excellent localization and retention of the designed nano-system at tumor tissues with targeting ratio of 9.0. CONCLUSION: Stirred a new candidate tumor theragnostic agent that is safe, selective and stable.

Discovery of novel benzofuran-based derivatives as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease: Design, synthesis, biological evaluation, molecular docking and 3D-QSAR investigation.

A series of novel benzofuran-based compounds 7a-s were designed, synthesized, and investigated in vitro as acetylcholinesterase inhibitors (AChEIs). Compounds 7c and 7e displayed promising inhibitory activity with IC50 values of 0.058 and 0.086 µM in comparison to donepezil with an IC50 value of 0.049 µM. The new molecules' antioxidant evaluation revealed that 7c, 7e, 7j, 7n, and 7q produced the strongest DPPH scavenging activity when compared to vitamin C. As it was the most promising AChEI, compound 7c was selected for further biological evaluation. Acute and chronic toxicity studies exhibited that 7c showed no signs of toxicity or adverse events, no significant differences in the blood profile, and an insignificant difference in hepatic enzymes, glucose, urea, creatinine, and albumin levels in the experimental rat group. Furthermore, 7c did not produce histopathological damage to normal liver, kidney, heart, and brain tissues, ameliorated tissue malonaldehyde (MDA) and glutathione (GSH) levels and reduced the expression levels of the APP and Tau genes in AD rats. Molecular docking results of compounds 7c and 7e showed good binding modes in the active site of the acetylcholinesterase enzyme, which are similar to the native ligand donepezil. 3D-QSAR analysis revealed the importance of the alkyl group in positions 2 and 3 of the phenyl moiety for the activity. Overall, these findings suggested that compound 7c could be deemed a promising candidate for the management of Alzheimer's disease.

Anti-Alzheimer activity of new coumarin-based derivatives targeting acetylcholinesterase inhibition.

New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC50 value of 0.802 µM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil.

New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies.

The current work represents the design and synthetic approaches of a new set of compounds 6-10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold. The biological evaluation revealed that most of the new compounds were promising selective dipeptidyl peptidase-IV (DPP-4) inhibitors and in vivo hypoglycemic agents utilizing linagliptin as a standard drug. The acute toxicity examination confirmed the safety profile of all compounds. Molecular docking studies related the significant DPP-4 suppression activity of compounds 9a, 10a, 10f, 10g to their nice fitting in the active pocket of DPP-4. In addition, the molecular dynamic study exhibited the stability of both 10a and 10g within the active site of DPP-4. The QSAR study showed that the difference between the predicted activities is very close to the experimental suppression effect. Moreover, both compounds 10a and 10g obeyed Lipinski's rule, indicating their efficient oral bioavailability. Compound 10a was radiolabeled, forming the 131I-SQ compound 10a to study the pharmacokinetic profile of this set of compounds. The biodistribution pattern hit the target protein since the tracer accumulated mainly in the visceral organs where DPP-4 is secreted in a high-level, thus with consequent stimulation of insulin secretion, leading to the target hypoglycemic effect.

Development of Promising Thiopyrimidine-Based Anti-cancer and Antimicrobial Agents: Synthesis and QSAR Analysis.

Objective & Methodology: New hybrids of thiopyrimidine-five/six heterocyclic rings were synthesized and in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HCT116 (human colorectal carcinoma), PC-3 (human prostate adenocarcinoma) and HepG2 (human liver carcinoma) cell lines. The most potency was elicited by the target candidates against the viability of HCT116 cell lines. It was higher than that obtained by the positive control 5-Fluorouracil (IC50 range; 0.11-0.49 µM, IC50, 5-FU; 1.10 µM). Results: Cell cycle analysis and apoptosis activation revealed that compound 20 induced G2/M phase arrest and apoptosis in HCT116 cells. In addition, compound 20 activates the caspases-9 and -3, a process which might mediate the apoptosis of HCT116 cells. Quantitative structure activity relationship study was done and revealed a high predictive power R2 suggesting goodness of the models. Conclusion: Furthermore, there is a good agreement between the observed pIC50 and the predicted pIC50 values, in addition, the low RMSD and standard error values indicate the accuracy of the model. Antimicrobial evaluation revealed that some of these compounds exhibited significant activities against the tested pathogenic bacteria and fungi, wherein compounds 7a, 14, 15a, 21a, produced the most potent and broad spectrum antibacterial and antifungal potency that was equivalent to that revealed by Vibramycin and Ketoconazole (MIC; 125 µg/mL). Moreover, compounds 15a, 21c, investigated dual potent antimicrobial and anticancer activity.

Design, Synthesis and Biological Evaluation of Spiro Cyclohexane-1,2- Quinazoline Derivatives as Potent Dipeptidyl Peptidase IV Inhibitors.

OBJECTIVE: Inhibition of dipeptidyl peptidase IV (DPP-4) is currently one of the most valuable and potential chemotherapeutic regimes for the medication of Type 2 Diabetes Mellitus (T2DM). METHOD: Based on linagliptin, this study discusses the design, synthesis and biological evaluation of spiro cyclohexane-1,2'-quinazoline scaffold hybridized with various heterocyclic ring systems through different atomic spacers as a highly potent DPP-4 inhibitors. DPP-4 enzyme assay represented that most of the target compounds are 102-103 folds more active than the reference drug linagliptin (IC50: 0.0005-0.0089 nM vs 0.77 nM; respectively). Moreover, in vivo oral hypoglycemic activity assay revealed that most of the tested candidates were more potent than the reference drug, sitagliptin, producing rapid onset with long duration of activity that extends to 24 h. Interestingly, the derivatives 11, 16, 18a and 23 showed evidence of mild cytochrome P450 3A4 (CYP3A4) inhibition (IC50; > 210 µM) and their acute toxicity (LD50) was more than 1.9 gm/kg. Molecular simulation study of the new quinazoline derivatives explained the obtained biological results. CONCLUSION: Finally, we conclude that our target compounds could be highly beneficial for diabetic patients in the clinic.