Utility of sulfachloropyridazine in the synthesis of novel anticancer agents as antiangiogenic and apoptotic inducers.

In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site.

Quinazoline sulfonamide derivatives targeting MicroRNA-34a/MDM4/p53 apoptotic axis with radiosensitizing activity.

Aim: New quinazoline benzenesulfonamide hybrids 4a-n were synthesized to determine their cytotoxicity and effect on the miR-34a/MDM4/p53 apoptotic pathway. Materials & methods: Cytotoxicity against hepatic, breast, lung and colon cancer cell lines was estimated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: Compound 4d was the most potent against HepG2 and MCF-7 cancer cells, with potential apoptotic activity verified by a significant upregulation of miR-34a and p53 gene expressions. The apoptotic effect of 4d was further investigated and showed downregulation of miR-21, VEGF, STAT3 and MDM4 gene expression. Conclusion: The anticancer and apoptotic activities of 4d were enhanced post irradiation by a single dose of 8 Gy γ-radiation. Docking analysis demonstrated a valuable affinity of 4d toward VEGFR2 and MDM4 active sites.

Novel iodoquinazolinones bearing sulfonamide moiety as potential antioxidants and neuroprotectors.

In a search for new antioxidants, a set of new iodoquinazolinone derivatives bearing benzenesulfonamide moiety and variable acetamide pharmacophores 5-17 were designed and synthesized. The structures of the synthesized compounds were confirmed based on spectral data. Compounds 5-17 were screened using in vitro assay for their antioxidant potential and acetylcholinesterase (AChE) inhibitory activity. The 2-(6-iodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-ylthio)-N-(pyrazin-2-yl) acetamide 14 was the most active scaffold with potent AChE inhibitory activity. Compound 14 showed relative safety with a median lethal dose of 300 mg/kg (LD50 = 300 mg/kg), in an acute toxicity study. The possible antioxidant and neuroprotective activities of 14 were evaluated in irradiated mice. Compound 14 possessed in vivo AChE inhibitory activity and was able to modify the brain neurotransmitters. It was able to cause mitigation of gamma radiation-induced oxidative stress verified by the decline in Myeloperoxidase (MPO) and increase of glutathione (GSH) levels. Also, 14 restored the alterations in behavioral tests. Molecular docking of 14 was performed inside MPO and AChE active sites and showed the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings would support that 14 could be considered a promising antioxidant with a neuromodulatory effect.

New quinazoline sulfonamide derivatives as potential anticancer agents: Identifying a promising hit with dual EGFR/VEGFR-2 inhibitory and radiosensitizing activity.

Herein, we report the synthesis of a series of new quinazoline sulfonamide conjugates 2-16 and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. The compounds were evaluated for their cytotoxicity against four cancer cell lines (HepG2, MCF-7, HCT116 and A549) using MTT assay. The most active compounds were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Compound 15 showed the most significant cytotoxic activity with IC50 = 0.0977 µM against MCF-7 and the most potent inhibitory activity against both EGFR and VEGFR with IC50 = 0.0728 and 0.0523 µM, respectively. Compound 15 was able to induce apoptosis in MCF-7 cells and cell cycle arrest at the G2/M phase. The relative safety profile of 15 was assessed using HEK-293 normal cell line and an ADMET profile was carried out. Radiosensitizing evaluation of 15 proved its significant ability to sensitize the cancer cell to the effect of radiation after being subjected to a single dose of 8 Gy gamma irradiation. Molecular docking studies revealed that 15 could bind to the ATP-binding site of EGF and VEGF receptors, inhibiting their activity.

Antimicrobial, anticancer and immunomodulatory potential of new quinazolines bearing benzenesulfonamide moiety.

Sulfonamides are privileged candidates with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and could replenish the MRSA antibiotic pipeline. The initial screening of a series of quinazolinone benzenesulfonamide derivatives 5-18 against multidrug-resistant bacterial and fungal strains revealed their potent activity. The promising compounds were conjugated with ZnONPs to study the effect of nanoparticle formation on the antimicrobial, cytotoxic and immunomodulatory activity. Compounds 5, 11, 16 and 18 revealed promising antimicrobial and cytotoxic activities with superior safety profiles and enhanced activity upon nanoformulation. The immunomodulatory potential of compounds 5, 11, 16 and 18 was assessed. Compounds 5 and 11 demonstrated an increase in spleen and thymus weight and boosted the activation of CD4+ and CD8+ T lymphocytes, confirming their promising antimicrobial, cytotoxic and immunomodulatory activity.

Antiproliferative, antiangiogenic and apoptotic effect of new hybrids of quinazoline-4(3H)-ones and sulfachloropyridazine.

Three new sets of quinazolinones bearing sulfachloropyridazine 4a-f, 6a-i and 8a-i were designed and synthesized. All the synthesized compounds were screened for their in vitro cytotoxicity against a panel of 60 cancer cell lines. The most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were evaluated as VEGFR-2 inhibitors. Compounds 8f, 8c and 6f were the most active with IC50 = 66 ± 0.002, 108 ± 0.004 and 146 ± 0.006 nM, respectively. Compound 8f showed also moderate inhibition against PDGFR (IC50 = 180 ± 0.009 nM), EGFR (IC50 = 98 ± 0.004 nM), FGFR-1 (IC50 = 82 ± 0.004 nM) and ability to reduce migration of cells in wound healing assay. Compound 8f showed cell cycle arrest at S-phase and induced early and late apoptosis in Annexien V-FITC assay. In addition, compound 8f increased the level of caspase-3 and up regulate Bax expression and down regulate Bcl-2 in UO-31 cells. The cytotoxicity of compounds 6f, 6g and 8f against UO-31 and melanoma cells was slightly affected by combination with γ-radiation. Also, compound 8f showed low toxicity against human normal renal (RPTEC) cell line. Docking studies of the most potent compounds 4b, 4d, 6f, 6g, 8c, 8f and 8g were performed to have more insights on their binging mode within VEGFR-2 active site.

Induction of apoptosis, cytotoxicity and radiosensitization by novel 3,4-dihydroquinazolinone derivatives.

Twenty new quinazolinone derivatives bearing a piperonyl moiety were designed and synthesized. The structures of the target compounds were in agreement with the microanalytical and spectral data. Compounds 4-10, 13, 14 and 17-27 were screened for their cytotoxic activity against HepG-2 and MCF-7 cancer cell lines. The target compounds showed IC50 in the range of 2.46-36.85 µM and 3.87-88.93 µM for HepG-2 and MCF-7, respectively. The promising compounds 7, 19, 26 and 27 were selected to measure their EGFR inhibitory activity. The IC50 values of the promising compounds were in the range of 146.9-1032.7 nM for EGFR in reference to Erlotinib (IC50 = 96.6 nM). In further studies on compounds 7, 19, 26 and 27 using HepG-2 cell line, there was significant overexpression of p21 and downregulation of two members of IAPs protein family; Survivin and XIAP, relative to their controls. Annexin V-FITC and caspase-3 analyses have established a significant increase in early apoptosis. Moreover, the four selected compounds have impaired cell proliferation by cell cycle arrest at the G2/M phase compared to their respective control. Considering radiotherapy as the primary treatment for many types of solid tumors, the radiosensitizing abilities of compounds 7, 19, 26 and 27 were measured against HepG-2 and MCF-7 cell lines combined with a single dose of 8 Gy gamma radiation. Measurement of the IC50 of the promising compounds after irradiation revealed their ability to sensitize the cells to the lethal effect of gamma irradiation (IC50 = 1.56-4.32 µM and 3.06-5.93 µM for HepG-2 and MCF-7 cells, respectively). Molecular docking was performed to gain insights into the ligand-binding interactions of 7, 19, 26 and 27 inside the EGFR binding sites and revealed their essential interactions, explaining their good activity towards EGFR.

Novel iodinated quinazolinones bearing sulfonamide as new scaffold targeting radiation induced oxidative stress.

Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC50 = 28 µM) and in vivo median lethal dose (LD50) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation.

Biological evaluation, radiosensitizing activity and structural insights of novel halogenated quinazoline-sulfonamide conjugates as selective human carbonic anhydrases IX/XII inhibitors.

A library of iodoquinazolinones endowed with benzenesulfonamide moiety was designed and synthesized as human carbonic anhydrase (hCA) inhibitors. Compounds 4-17 showed generally poor activity against the cytosolic hCA I and hCA II isoforms. Contrarily they were more potent and showed a variable spectrum of selectivity against the tumor-specific isoforms hCA IX and hCA XII. The 4-iodophenyl derivative 12 and the 4-pyridinyl derivative 15 were the most active and selective in this series against hCA IX and hCA XII isoforms with KI of 18 and 9 nM, respectively. Compounds 12 and 15 were further screened for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines besides WI38 and MCF-10A normal cell lines to determine their selectivity towards cancer cells. Compound 12 was selective towards HepG-2 and HCT-116 cell lines but less selective towards MCF-7. While compound 15 showed higher selectivity towards HepG-2 than HCT-116 and MCF-7 cell lines. The ability of compounds 12 and 15 to sensitize the cells against gamma irradiation's effect proved their potential radiosensitizing activity. Molecular docking analysis was carried out to discover the possible binding mode of the compounds within the active site of isoform hCA IX and XII. Compounds 12 and 15 revealed the probable fundamental interactions explaining the good activity and selectivity towards the tumor-specific isoforms.

Synthesis of some quinazolinones inspired from the natural alkaloid L-norephedrine as EGFR inhibitors and radiosensitizers.

A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.

Iodoquinazolinones bearing benzenesulfonamide as human carbonic anhydrase I, II, IX and XII inhibitors: Synthesis, biological evaluation and radiosensitizing activity.

In the present work, we report the design and synthesis of a set of iodinated quinazolinones carrying benzenesulfonamide moiety as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The target compounds showed promising inhibitory activity against the four examined human (h) CA isoforms; I, II, IX and XII. Compounds 4-18 displayed variable inhibition constants, ranging as follows: 7.6-782.8 nM for hCA I, 34.4-412.1 nM for hCA II, 29.1-2225.3 nM for hCA IX and 8.8-429.4 nM for hCA XII. Compound 9, the most potent against the tumor-specific CA IX/CA XII (KI = 29.1 and 8.8 nM) gives the possibility to evaluate its cytotoxicity and selectivity in vitro against HepG-2, HCT-116 and MCF-7 cancer cell lines. Compound 9 showed significant cytotoxicity against the tumor cell lines (IC50 = 1.78, 1.94 and 3.07 µM, respectively) and relatively lower toxicity against WI38 normal cell line. The radiosensitizing activity of compound 9 was evaluated and displayed an increase in the radiation-induced cell death in cancer cells after receiving a single dose of 8 Gy gamma radiation. Thus, radiation was able to enhance the antiproliferative activity of compound 9. Molecular docking of 9 into the active site of CA IX and XII revealed the key interactions that could explain its potent activity and selectivity towards these isoforms.

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety.

Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4-18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro. Compound 15 had low toxicity in mice (LD50 = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.

Novel N-(Substituted) Thioacetamide Quinazolinone Benzenesulfonamides as Antimicrobial Agents.

AIM: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. MATERIALS AND METHODS: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. RESULTS: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. CONCLUSION: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.

Antioxidant activity of novel quinazolinones bearing sulfonamide: Potential radiomodulatory effects on liver tissues via NF-κB/ PON1 pathway.

In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. The N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide 16 was the most active scaffold in this series with greater scavenging activity than that of ascorbic acid. In vivo acute toxicity study of compound 16 indicates its relative safety with a median lethal dose of 200 mg/kg. The possible antioxidant and hepatoprotective activities of compound 16 were evaluated in irradiated mice. Compound 16 caused mitigation of gamma radiation-induced oxidative stress verified by the decline in MDA, ROS and NF-κB levels. Moreover, SOD and PON1 activities, as well as Zn2+ levels, were improved in liver tissues. Furthermore, molecular docking of compound 16 inside the active site of SOD and PON1 demonstrated the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings support that compound 16 may represent a structural lead for developing new antioxidants and hepatoprotective agents.

Novel sulphonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers.

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.

Exploration of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives as anticancer and radiosensitizing agents.

Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5-18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC50 in the range of 0.34-149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09-20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC50 of the promising compounds were in the range of 247-793 nM for VEGFR-2 in reference to sunitinib (IC50 320 nM), and 369-725 nM for EGFR in reference to erlotinib (IC50 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC50 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC50 of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands.

Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers.

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5-18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC50 of all the compounds were in the range of 0.36-40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00-16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC50 in the range of 0.64-1.81 µM for EGFR and 1.13-2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors.

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5-19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5-19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC50 ranging from 0.009 to 0.026 µM for EGFR and 0.021 to 0.069 µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC50 0.009 and 0.021 µM for EGFR and HER2, respectively.

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety.

BACKGROUND: A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3a-t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs. RESULTS: Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL). CONCLUSION: The structure-activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.

Discovery of Benzo[g]quinazolin benzenesulfonamide derivatives as dual EGFR/HER2 inhibitors.

An array of some new N-(substituted)-2-((4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)acetamide 5-19 were synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl)benzenesulfonamide 4, to be assessed for their cytotoxic activity against A549 lung cancer cell line and to determine their inhibitory effect on EGFR tyrosine kinase enzyme. Compounds 5-19 showed high activity towards A549 cell line with IC50 values of 0.12-8.70 µM. Compounds 6, 12 and 18 were the most potent in this series. These compounds were further screened as dual inhibitors for EGFR/HER2 enzymes in comparison with erlotinib and were found to possess very potent activity. Compound 12 showed the highest activity with IC50 values of 0.06 µM and 0.30 µM towards EGFR and HER2, respectively. Accordingly, the apoptotic effect of the most potent compounds 6, 12 and 18 was investigated and showed a marked increase in the level of caspases-3 by 6, 9 and 8 folds, respectively, compared to the control cells. Moreover, Molecular modeling was performed inside the active site of EGFR, keeping in mind their binding possibilities, bond lengths, angles and energy scores. It was found that the most active compounds demonstrated the best binding scores in the active site of EGFR, which may clarify their high inhibition profile.