2-Thioxo-3,4-dihydropyrimidine and thiourea endowed with sulfonamide moieties as dual EGFRT790M and VEGFR-2 inhibitors: Design, synthesis, docking, and anticancer evaluations.

The effectiveness of a new series of thiopyrimidine and thiourea containing sulfonamides moieties was tested on HCT-116, MCF-7, HepG2, and A549. HepG2 cell line was the one that all the new derivatives affected the most. The greatest potent compounds against the four HepG2, HCT116, MCF-7, and A549 cell lines were 8f and 8g with IC50 = 4.13, 6.64, 5.74, 6.85 µM and 4.09, 4.36, 4.22, 7.25 µM correspondingly. Compound 8g exhibited higher activity than sorafenib against HCT116 and MCF-7 but exhibited lower activity against HepG2 and A549. Moreover, compounds 8f and 8g exhibited higher activities than erlotinib on HepG2, HCT116, and MCF-7 but demonstrated lower activity on A549. The most potent cytotoxic derivatives 6f, 6g, 8c, 8d, 8e, 8f, and 8g were examined on normal VERO cell lines. Our derivatives have low toxicity on VERO cells with IC50 values ranging from 32.05 to 53.15 µM. Additionally, all compounds were assessed for dual VEGFR-2 and EGFRT790M inhibition effects. Compounds 8f and 8g were the most potent derivatives inhibited VEGFR-2 at IC50 value of 0.88 and 0.90 µM, correspondingly. As well, derivatives 8f and 8g could inhibit EGFRT790M demonstrating strongest effects with IC50 = 0.32 and 0.33 µM sequentially. Additionally, the greatest active derivatives ADMET profile was evaluated in relationship with sorafenib and erlotinib as reference agents. The data attained from docking were greatly related to that achieved from the biological testing.

Synthesis and Characterization of a New Class of Chromene-Azo Sulfonamide Hybrids as Promising Anticancer Candidates with the Exploration of Their EGFR, hCAII, and MMP-2 Inhibitors Based on Molecular Docking Assays.

In this study, novel selective antitumor compounds were synthesized based on their fundamental pharmacophoric prerequisites associated with EGFR inhibitors. A molecular hybridization approach was employed to design and prepare a range of 4H-chromene-3-carboxylates 7a-g, 8, and 11a-e derivatives, each incorporating a sulfonamide moiety. The structures of these hybrid molecules were verified using comprehensive analytical and spectroscopic techniques. During the assessment of the newly synthesized compounds for their anticancer properties against three tumor cell lines (HepG-2, MCF-7, and HCT-116), compounds 7f and 7g displayed remarkable antitumor activity against all tested cell lines, outperforming the reference drug Cisplatin in terms of efficacy. Consequently, these promising candidates were selected for further investigation of their anti-EGFR, hCAII, and MMP-2 potential, which exhibited remarkable effectiveness against EGFR and MMP2 when compared to Sorafenib. Additionally, docking investigations regarding the EGFR binding site were implemented for the targeted derivatives in order to attain better comprehension with respect to the pattern in which binding mechanics occur between the investigated molecules and the active site, which illustrated a higher binding efficacy in comparison with Sorafenib.

A new class of anti-proliferative activity and apoptotic inducer with molecular docking studies for a novel of 1,3-dithiolo[4,5-b]quinoxaline derivatives hybrid with a sulfonamide moiety.

A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their in vitro anticancer activity. The structures of the novel compounds were systematically characterized by 1H NMR, 13C NMR, and elemental analysis. The synthesized derivatives were evaluated for their in vitro antiproliferative activity against three human cancer cell lines (HepG-2, HCT-116, and MCF-7) with more sensitivity to MCF-7. Moreover, three derivatives 10c, 10f, and 12 were the most promising candidates with sub-micromole values. These derivatives were further evaluated against MDA-MB-231, and the results displayed significant IC50 values ranging from 2.26 ± 0.1 to 10.46 ± 0.8 µM and showed low cellular cytotoxicity against WI-38. Surprisingly, the most active derivative 12 revealed sensitivity towards the breast cell lines MCF-7 (IC50 = 3.82 ± 0.2 µM) and MDA-MB-231 (IC50 = 2.26 ± 0.1 µM) compared with doxorubicin (IC50 = 4.17 ± 0.2 and 3.18 ± 0.1 M). Cell cycle analysis showed that compound 12 arrests and inhibits the growth of MCF-7 cells in the S phase with values of 48.16% compared with the untreated control 29.79% and exhibited a significantly higher apoptotic effect in MCF-7 with a value of 42.08% compared to control cell at 1.84%. Furthermore, compound 12 decreased Bcl-2 protein 0.368-fold and activation on pro-apoptotic genes Bax and P53 by 3.97 and 4.97 folds, respectively, in MCF-7 cells. Compound 12 exhibited higher inhibitory activity to EGFRWt, EGFRL858R, and VEGFR-2 with IC50 values (0.19 ± 0.009, 0.026 ± 0.001, and 0.42 ± 0.021 µM) compared with erlotinib (IC50 = 0.037 ± 0.002 and 0.026 ± 0.001 µM) and sorafenib (IC50 = 0.035 ± 0.002 µM). Finally, in silico ADMET prediction presented that 1,3-dithiolo[4,5-b]quinoxaline derivative 12 obeys the Lipinski rule of five and the Veber rule with no PAINs alarms and moderately soluble properties. Additionally, toxicity prediction revealed that compound 12 demonstrated inactivity to hepatotoxic carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Moreover, molecular docking studies showed good binding affinity with lower binding energy inside the active site of Bcl-2 (PDB: 4AQ3), EGFR (PDB: 1M17), and VEGFR (PDB: 4ASD).

DFT and In-silico Investigations, along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules.

BACKGROUND: Molecules bearing an active methylene bridge are one of the most fruitful and remarkable precursors that have been incorporated into the synthetic strategy of an assortment of bioactive compounds. OBJECTIVE: The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and result from their structural diversity and discrete reactivity. METHODS: The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acids, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug-likeness predictions were conducted for all the synthesized compounds. RESULTS: The highest docking score is -9.9 and -8.3 kcal/mol, respectively, for compound 9 (azocoumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e., more than -8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell lines and the hemolytic effect on RBCs. CONCLUSION: The in-silico ADMET studies of the synthesized compounds revealed moderate to good -likeness, high gastro intestinal (GI) absorption, and inhibiting the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density functional theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gaps, dipolemoment, andmolecular electrostatic potential. Such parameters, along with the physicochemical parameters, could be a good tool to confirm biological activity.

A novel spectrofluorimetric method based on a reaction with an azoisoxazoles-benzenesulfonamide derivative for determination of uranium (VI) ions in water samples.

Selective fluorometric detection and determination of uranium ions is provided here using a novel fluorescent reagent, namely (E)-4-([4-hydroxynaphthalen-1-yl]diazenyl)-N-(5-methyleisoxazol-3-yl) benzenesulfonamide (UVI reagent). The UVI reagent offers a selective fluorescence enhancement behaviour at emission wavelength = 557 nm. The parameters affecting fluorometric detection of uranium ions, such as the pH, solvent type, ligand concentration, interaction time, and interfering ions, were investigated and adjusted. The proposed UVI reagent can detect and determine uranium ions even at low concentrations, for which the obtained limit of detection was 0.1 ppm. Additionally, this proposed determination protocol was successfully used to detect, monitor, and determine uranium ions in actual water samples.

Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors.

A new series of sulfonamide endowed with hydrazone coupled to dimethyl and/or diethyl malonates were prepared. Various sulfa drugs were diazotized and followed by coupling with active methylene of dimethyl and/or diethyl malonate to afford the new intermediates hydrazones 3a-c and 4a-c. The reactivity of hydrazone derivatives towards hydrazines was investigated. Thus, a novel series of 3,5-dioxopyrazolidine7a-cwere obtained by treatment with hydrazine hydrate. When hydrazones were allowed to react with phenyl hydrazine, the alkyl 2-((4-(N-(substituted)sulfamoyl)phenyl)diazenyl)-3-oxo-3-(2-phenylhydrazinyl)propanoateswere obtained 8a-c and/or 10a-c. Their anticancer activities were evaluated against HepG2, HCT-116 and MCF-7. HepG2 was the most sensitive one. In particular, compounds 7c, 7b and 10c were found to be the most potent derivatives with IC50 = 6.43 ± 0.5, 9.66 ± 0.8, 10.57 ± 0.9 µM, 8.65 ± 0.7, 7.49 ± 0.6, 14.29 ± 1.3 µM and 8.97 ± 0.7, 10.13 ± 0.9, 13.82 ± 1.1 µM respectively. Sorafenib and doxorubicin were used as reference drugs. The most potent derivatives 7a, 7b, 7c, 8c and 10c were tested for their cytotoxicity against normal VERO cell lines. Compounds 7a, 7b, 7c, 8c and 10c are respectively, 2.41, 4.85, 4.08, 3.23 and 5.89 fold times more toxic in HCT116 than in VERO normal cells. Moreover, the most active anti-proliferative derivatives 7a, 7b, 7c, 8c and 10c were subjected to further biological study to evaluate their inhibitory potentials against VEGFR-2. The tested compounds displayed high to good inhibitory activity with IC50 values ranging from 0.14 ± 0.02 to 0.23 ± 0.03 µM. Among them, compounds 7c, 7b and 10c were found to be the most potent derivative that inhibited VEGFR-2 at IC50 values of 0.14 ± 0.02, 0.15 ± 0.02 and 0.15 ± 0.02 µM respectively. sorafenib was used as reference drug. Furthermore, ADMET profile was evaluated for the four most active compounds in comparison to doxorubicin as a reference drug. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

Design, green synthesis, molecular docking and anticancer evaluations of diazepam bearing sulfonamide moieties as VEGFR-2 inhibitors.

Novel series of diazepam bearing sulfonamide moieties 5a-f and 7a-c were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5d was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = 8.98 ± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5d exhibited higher activity than sorafenib, (IC50 = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell lines respectively. Compounds 5b, 5c, 5d, 5e, 5f and 7c are respectively, 5.77, 8.58, 9.54, 5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most sensitive cells) than in VERO normal cells. All the synthesized compounds 5a-f and 7a-c were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5d was found to be the most potent derivative that inhibited VEGFR-2 at IC50 value of 0.10 ± 0.01 µM, which is equipotent to sorafenib IC50 value (0.10 ± 0.02 µM). Compound 5c exhibited excellent activity with IC50 value of 0.12 ± 0.01 µM which nearly equipotent to that of sorafenib. Compounds 5b, 5e and 5f exhibited very good activity with the same IC50 value of 0.14 ± 0.02 µM. Also, compounds 7c and 7b possessed good VEGFR-2 inhibition with IC50 values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the half activity of that of sorafenib. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

First example of Azo-Sulfa conjugated chromene moieties: Synthesis, characterization, antimicrobial assessment, docking simulation as potent class I histone deacetylase inhibitors and antitumor agents.

This report presents the development of a novel and primary model of sulfonamide compounds encompassing a chromene azo motif with the intent of becoming applicable for drug candidates in the cases of drug-resistant pathogens. The novel molecules (7a-n) have been synthesized via a two-step reaction. First, 4-((2, 4-dihydroxyphenyl)diazenyl)benzenesulfonamide (3a-e) were obtained through the reaction of their corresponding diazotized 4-aminobenzenesulfonamides (1a-e) with resorcinol, followed by the heterocyclization of 3a-e with arylidenemalononitriles (6a-d). Upon structural identification, the newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Moreover, their cytotoxic screening was performed against three cancer cell lines: HCT-116, HepG-2, and MCF-7. Further examinations were comprised of the inhibitory effect analyses of the novel sulfonamide/chromene derivatives against the HDAC classes and the Tubulin polymerization in order to discern the prime antitumor drug candidates.

Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking.

BACKGROUND: Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. RESULTS: A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 µg/mL. Molecular docking was performed on the active site of MK-2 with good results. CONCLUSION: Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.

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.

Novel Thiourea Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Through COX-2 Inhibition.

BACKGROUND: Thiourea derivatives bearing sulfonamide moiety are well known for their anticancer activity. OBJECTIVE: The anticancer activity of the target compounds was studied, via inhibition of COX-2 enzyme. METHOD: A series of novel thioureas 5a-n, 8, quinazoline 6, benzo[g]quinazoline 7 and benzo[1,3] dioxole 10, bearing a sulfonamide moiety was synthesized from the starting compound N-(2,6-dimethoxypyrimidin-4-yl)-4- isothiocyanatobenzenesulfonamide 2. The target compounds were screened against HepG2, MCF-7, Caco-2, HCT-116, PC-3 cancer cell lines and VERO-B normal cell line. RESULTS: Out of all the tested compounds, compound 5c showed a broad selective cytotoxicity against HepG2, MCF-7, Caco-2 and PC-3 cancer cells. Moreover, a sensitization assay was performed on Caco-2 cells, and compound 5c proved to act as a chemosensitizer for cisplatin on colon cancer (Caco-2) cells. The target compounds were further screened in vitro for their anti COX1/COX2 activity and investigated in vivo as antiinflammatory agents against carrageenan-induced rat paw oedema model. CONCLUSION: Compound 5g showed the most selective inhibitory activity against COX-2. While, compounds 5a, 6, 5m, 5n, 5g and 5i revealed significant anti-inflammatory effect as presented in carrageenan-induced oedema assay. Molecular docking of the tested compounds disclosed important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme.

Biological evaluation of some new N-(2,6-dimethoxypyrimidinyl) thioureido benzenesulfonamide derivatives as potential antimicrobial and anticancer agents.

A series of novel heterocyclic thioureas 3a-u containing sulfonamide moiety have been synthesized by the condensation of isothiocyanatobenzenesulfonamide 2 with a variety of heterocyclic amines. The newly synthesized heterocyclic thioureas were investigated for their antimicrobial and anticancer activity. The in vitro antibacterial and antifungal activity were done using well diffusion method. Interestingly, compounds 3j and 3m, showed similar or better activity compared with the reference drug against the tested microorganisms. Although, 3j was less active among its analogues to inhibit the breast carcinoma cells, it exhibit strong broad spectrum antimicrobial activities. However, The results of the cytotoxic activity revealed that compound 3p was the most active against the breast carcinoma cell line (MCF-7) giving promising IC50 value of 1.72 µg/mL, compared with reference drug (5-flourouracil) with IC50 value of 4.8 µg/mL. The most potent compounds in cytotoxic activity 3b and 3p were further docked inside the active site of CAIX and were found to exhibit a proper binding with the active site amino acids according to their bond lengths, angles and conformational energy.

Synthesis, characterization and in vitro antimicrobial activity of novel 2-thioxo-4-thiazolidinones and 4,4'-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfones.

2-Thioxo-4-thiazolidinones (3a,b) were achieved by cyclocondensation of isothiocyanatosulfonamides (1a,b) with sulfanylacetic acid at reflux temperature in dioxane in the presence of triethylamine. Compound (3a) was exploited to synthesize the versatile hitherto unknown 2-thioxo-4-thiazolidinones (5-10) via its reaction with some electrophiles. Cyclization of 4,4'-diisothiocyanate diphenylsulfone (11) with sulfanylacetic acid furnished 4,4'-bis(2-thioxo-4-thiazolidinone-3-yl)diphenylsulfone (12) which on treatment with excess 4-methoxybenzaldehyde in refluxing dioxane in the presence of piperidine yielded the bisbenzylidene derivative (13). The novel synthesized compounds were characterized by IR, (1)H NMR and mass spectral studies. All the synthesized compounds were screened in vitro for their antibacterial and antifungal activities.

Novel antitumor acetamide, pyrrole, pyrrolopyrimidine, thiocyanate, hydrazone, pyrazole, isothiocyanate and thiophene derivatives containing a biologically active pyrazole moiety.

4-Amino-N-(1-phenyl-1H-pyrazol-5-yl)-benzenesulfonamide (sulfaphenazole) 1 was selected as strategic starting material for the synthesis of some novel acetamide 2, pyrrole 4, pyrrolo[2,3-d]pyrimidine 5, thiocyanate 6, hydrazone 7a,b pyrazole 8, isothiocyanate 9 and thiophene 12 derivatives to evaluate theantitumor activity. Compound 4 was more effective than the reference drug, doxorubicin (CAS 23214-92-8) as positive control.