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.

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.

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.

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.

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.

Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran-pyrazole derivatives as anticancer agents.

This study deals with design and synthesis of novel benzofuran-pyrazole hybrids as anticancer agents. Eight compounds were chosen by National Cancer Institute (NCI), USA to evaluate their in vitro antiproliferative activity at 10(-5)M in full NCI 60 cell panel. The preliminary screening of the tested compounds showed promising broad-spectrum anticancer activity. Compound 4c was further assayed for five dose molar ranges in full NCI 60 cell panel and exhibited remarkable growth inhibitory activity pattern against Leukemia CCRF-CEM, MOLT-4, Lung Cancer HOP-92, Colon Cancer HCC-2998, CNS Cancer SNB-75, Melanoma SK-MEL-2, Ovarian Cancer IGROV1, Renal Cancer 786-0, RXF 393, Breast Cancer HS 578T and T-47D (GI50: 1.00-2.71µM). Moreover, enzyme assays were carried out to investigate the possible antiproliferative mechanism of action of compound 4c. The results revealed that compound 4c has good c-Src inhibitory activity at 10µM. In addition, molecular docking studies showed that 4c could bind to the ATP Src pocket sites. Fulfilling the Lipinskiís rule of five in addition to its ADME profile and the biological results, all strongly suggest that 4c is a promising Src kinase inhibitor.

Novel benzimidazole derivatives as expected anticancer agents.

A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1-methyl analogues 2c-h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, carbon disulfide and/or thiosemicarbazide to yield compounds 11-19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiff's bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly synthesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocytoma of the rat adrenal medulla) cells. Benzimidazole-2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells.