Quinazoline-oxindole hybrids as angiokinase inhibitors and anticancer agents: Design, synthesis, biological evaluation, and molecular docking studies.

Two new sets of quinazoline-oxindole 8a-l and quinazoline-dioxoisoindoline 10a-d hybrids were designed as type II angiokinase inhibitors and anticancer agents. The design strategy was adjusted to account for the quinazoline scaffold's placement in the target kinases' hinge region, where it would form hydrogen bonding and hydrophobic interactions with the important amino acids to stabilize it, and the amide group's occupation in the gate region, which would direct the oxindole scaffold toward the hydrophobic back pocket. The two sets of quinazolines 8a-l and 10a-d displayed pronounced inhibitory activity on VEGFR-2 (IC50 = 0.46-2.20 µM). The quinazoline-oxindole hybrids 8d, 8f, and 8h displayed IC50 = 0.46, 0.49, and 0.49 µM, respectively. Compound 8f demonstrated potent multikinase activity with IC50 values of 0.95 and 0.67 µM against FGFR-1 and BRAF, respectively. Additionally, compound 8f showed significant anticancer activity against National Cancer Institute's cancer cell lines, with GI50 reaching 1.21 µM. Analysis of the impact of compound 8f on the MDA-MB-231 cell line's cell cycle and apoptosis revealed that 8f stalled the cell cycle at the G2/M phase and promoted its necrosis.

Benzimidazole-oxindole hybrids: A novel class of selective dual CDK2 and GSK-3ß inhibitors of potent anticancer activity.

A new series of benzimidazole-oxindole hybrids 8a-x was discovered as dual cyclin-dependent kinase (CDK2) and glycogen synthase kinase-3-beta (GSK-3ß) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single-dose and five-dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC-1 cells with IC50 = 1.88-2.79 µM. In addition, the hybrids 8l, 8n, 8o, and 8p displayed potent antiproliferative activity on the MG-63 cell line (IC50 = 0.99-1.90 µM). Concurrently, the benzimidazole-oxindole hybrid 8v exhibited potent dual CDK2/GSK-3ß inhibitory activity with IC50 values of 0.04 and 0.021 µM, respectively. In addition, 8v displayed more than 10-fold higher selectivity toward CDK2 and GSK-3 ß over CDK1, CDK5, GSK-3α, vascular endothelial growth factor receptor-2, and B-rapidly accelerated fibrosarcoma. Screening of the effect of 8n and 8v on the cell cycle and apoptosis of PANC-1 and MG-63 cells displayed their ability to arrest their cell cycle at the G2-M phase and to potentiate the apoptosis of both cell lines. In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3ß revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a-x exhibit satisfactory drug-likeness properties for drug development.

Recent Advances in Structural Optimization of Quinazoline-Based Protein Kinase Inhibitors for Cancer Therapy (2021-Present).

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021-2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds.

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.

Development of a New Benzofuran-Pyrazole-Pyridine-Based Molecule for the Management of Osteoarthritis.

Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran-pyrazole-pyridine-based compound 8 with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound 8. The biological assays indicated that compound 8 produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound 8 is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials.

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-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.

Design, synthesis and molecular docking of new pyrazole-thiazolidinones as potent anti-inflammatory and analgesic agents with TNF-α inhibitory activity.

A new set of derivatives bearing pyrazole-methylenehydrazono-thiazolidinone scaffold 4-23 was designed, synthesized and confirmed by different spectroscopic means and elemental analyses. In-vivo anti-inflammatory and ulcerogenic evaluation was performed for all the newly synthesized derivatives using indomethacin, celecoxib and diclofenac as standard drugs. The compounds 5, 10, 15, 17, 21, 22 appeared to be the most promising candidates producing rapid onset and long duration of anti-inflammatory activity as well as promising GIT safety profile. Furthermore, analgesic evaluation revealed that the compounds 5, 10, 15 and 22 produced potent and long acting analgesia accompanied with significant inhibition of the inflammatory cytokine TNF-α level in comparison with the standard drugs. Molecular docking study of the latter derivatives was also carried out to rationalize their binding affinities and their modes of interactions with the active site of TNF-α.

Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D QSAR, Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies.

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r2 = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ΔG of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an IC50 of 0.0136 µM, 0.015 µM, and 0.054 µM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 µM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. 131I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i. 131I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.

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.

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors.

Deregulation of various protein kinases is considered as one of the important factors resulting in cancer development and metastasis, thus multi-targeting the kinase family is one of the most important strategies in current cancer therapy. This context represents the design and synthesis of two sets of derivatives bearing a pyrazoline-3-one ring conjugated either with a thieno[3,2-d]thiazole or with a dihydrothiazolo[4,5-d]thiazole scaffold via an NH linker, 3a-d and 5a-d respectively, using the pyrazolinone-thiazolinone derivative 1 as a key precursor. All the newly synthesized compounds were assessed in vitro for their anticancer activity against two cancer cell lines (MCF-7 and HepG-2). The safety profile of the most active cytotoxic candidates 1 and 3c was further examined against the normal cell line WI-38. The compounds 1 and 3c were further evaluated as multi-targeting kinase inhibitors against EGFR, VEGFR-2 and BRAFV600E, exhibiting promising suppression impact. Additionally, the latter compounds were investigated for their impact on cell cycle and apoptosis induction potential in the MCF-7 cell line. Moreover, the antimicrobial activity of all the new analogues was evaluated against a panel of Gram-positive and Gram-negative bacteria, yeast and fungi in comparison to streptomycin and amphotericin-B as reference drugs. Interestingly, both 1 and 3c showed the most promising microbial inhibitory effect. Molecular docking studies showed promising binding patterns of the compounds 1 and 3c with the prospective targets, EGFR, VEGFR-2 and BRAFV600E. Finally, additional toxicity studies were performed for the new derivatives which showed their good drug-like properties and low toxicity risks in humans.

Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors.

Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.

A Comparative Study of the Anticancer Activity and PARP-1 Inhibiting Effect of Benzofuran-Pyrazole Scaffold and Its Nano-Sized Particles in Human Breast Cancer Cells.

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8-5.7 nm) of the previously prepared benzofuran-pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP.

Design, synthesis and anticervical cancer activity of new benzofuran-pyrazol-hydrazono- thiazolidin-4-one hybrids as potential EGFR inhibitors and apoptosis inducing agents.

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies.

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.

Kinase Inhibitory Activities and Molecular Docking of a Novel Series of Anticancer Pyrazole Derivatives.

A series of novel 1,3,4-triarylpyrazoles containing different heterocycles has been prepared, characterized and screened for their in vitro antiproliferative activity against HePG-2, MCF-7, PC-3, A-549 and HCT-116 cancer cell lines. The biological results revealed that compound 6 showed the highest anticancer activity so it was subjected to a kinase assay study where it reduced the activity of several protein kinases including AKT1, AKT2, BRAF V600E, EGFR, p38α and PDGFRß at 100 µM using the radiometric or ADP-Glo assay method. Molecular docking simulation supported the initial kinase assay and suggested a common mode of interaction at the ATP-binding sites of these kinases, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further research.

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 modeling of new benzimidazoles as glutathione S-transferase inhibitors and anticancer agents.

AIM: Synthesis of novel glutathione S-transferases (GSTs) inhibitors constitutes a promising strategy in cancer treatment. Results & methodology: A new set of benzimidazoles clubbed with various heterocycles as GST inhibitors and anticancer agents were synthesized. The biological results proved the potential of the new compounds as GST inhibitors, specifically compounds 7 and 14 which produced more potency than ethacrynic acid by three- and tenfold, respectively. Most compounds exhibited promising cytotoxic activity against breast and colon cancer cell lines. Molecular modeling studies revealed that compounds 7 and 14 showed good binding with the amino acids of the GST protein. CONCLUSION: Both compounds 7 and 14 fulfilled the Lipinski's rule of five suggesting them as new promising GST inhibitors and anticancer agents.

Synthesis and 2D-QSAR Study of Active Benzofuran-Based Vasodilators.

A new series of 2-alkyloxy-pyridine-3-carbonitrile-benzofuran hybrids (4a-x) was synthesized. All the new derivatives were examined via the standard technique for their vasodilation activity. Some of the investigated compounds exhibited a remarkable activity, with compounds 4w, 4e, 4r, 4s, 4f and 4g believed to be the most active hits in this study with IC50 values 0.223, 0.253, 0.254, 0.268, 0.267 and 0.275 mM, respectively, compared with amiodarone hydrochloride, the reference standard used (IC50 = 0.300 mM). CODESSA PRO was employed to obtain a statistically significant 2-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) model describing the bioactivity of the newly synthesized analogs (N = 24, n = 4, R² = 0.816, R²cvOO = 0.731, R²cvMO = 0.772, F = 21.103, s² = 6.191 × 10-8).