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Graphical abstract Highlights • 2-Substituted thiobenzimidazoles were synthesized and screened against A498 cell line. • The best IC 50 value was for compound 4a with (IC 50 = 6.97 µM) compared to sunitinib. • Compound 4a affected G2/M phases basically and was proved as late apoptotic inducer. • Compound 4a revealed good inhibitory activity against c-Met kinase (IC 50 = 0.27 µM). • Docking of 4a at c-Met kinase active site demonstrated good binding interactions. • Compound 4a showed a suitable predicted ADME profile. Abstract Benzimidazole is an interesting scaffold constituting a main core in many anticancer agents against variable cell lines as Carbendazim (I) and Nocodazole (II). Accordingly, eighteen compounds of 2-((1H-benzoimidazol-2-yl)thio)-1-(aryl/heteroaryl)ethan-1-ones, in their sulfate salt and free forms, were designed and investigated as anticancer agents. In vitro preliminary screening of selected compounds by the National Cancer Institute (NCI) on a panel of 60 cell lines revealed renal cancer cell line (A498) as the most vulnerable cell line; accordingly, IC 50 values against A498 cell line were determined for compounds with the best results. The best inhibitory activity was for compound 4a with (IC 50 = 6.97 µM) compared to sunitinib as a reference drug (IC 50 = 6.99 µM). Compound 4a was further subjected to cell cycle analysis that indicated the decrease in cell population in the G2/M phase when compared to the untreated control cells. In addition, it showed significant increase in the late apoptosis in Annexin-V FTIC study compared to the control cells. An enzymatic inhibitory study on compound 4a against c-Met and MAP kinases revealed its better activity against c-Met kinase with (IC 50 = 0.27 µM) compared to sunitinib (IC 50 = 0.18 µM). Molecular docking study was conducted to reveal the interactions of compound 4a in the active site of c-Met kinase. Computational ADME study was performed to insure that compound 4a has proper pharmacokinetic and drug-likeness properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • - Different sets of coumarin-sulfonamide, coumarin-carboxylic acid and coumarin derivatives were synthesized. • - Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms. • - Coumarin-sulfonamides displayed superior hCA IX/XII inhibitory activities (K I s: 3.4–59 nM). • - Coumarins 9a - b exhibited excellent hCA IX/XII selectivity (SIs > 1000) over hCA I and II. • - Coumarin 9a showed promising anticancer activities against and MCF-7 cancer cell lines. Recently, different mechanisms for inhibition of carbonic anhydrases (CAs) have been reported, such as the classical zinc-binding (exerted by sulfonamides and carboxylic acids) as well as occluding the entrance of the CA active site (exerted by coumarins). In this manuscript, we studied the effect of combining the pharmacopheric parts responsible for these two mechanisms on CA inhibitory potency and selectivity through the design and synthesis of novel coumarins tethered with the zinc-binding sulfonamide (5a-f , 11a-b and 13a-b) or carboxylic acid (7a-f) groups. In addition, another set of coumarin derivatives (9a-b) with no zinc-binding group (ZBG) was designed to act as non-classical CA inhibitors. The synthesized coumarins were examined for their inhibitory activities towards four hCA isoforms I, II, IX and XII. Coumarin sulfonamides (5a-f , 11a-b and 13a-b) effectively inhibited both tumor-associated hCA IX (K I s: 8.9–133.5 nM) and hCA XII (K I s: 3.4–42.9 nM) isoforms, whereas coumarin carboxylic acids (7a-f) weakly affected hCA IX (K I s: 0.49–11.2 μM) and hCA XII (K I s: 0.51–10.1 μM) isoforms. The coumarin based inhibitors featuring zinc-binding sulfonamide or carboxylic acid group achieved low to moderate hCA IX/XII selectivity. Interestingly, the ZBG-free coumarin derivatives (9a-b) emerged not only as effective hCA IX (K I s = 93.3 and 63.8 nM, respectively) and hCA XII (K I s = 85.7 and 72.1 nM, respectively) inhibitors, but also as a highly hCA IX/XII selective inhibitors over the off-target h CA I/II isoforms (SIs > 1000). Coumarin 9a was further evaluated for its anti-proliferative effect on MCF-7 and PANC-1 cancer cell lines, as well as its effect on the cell cycle and apoptosis towards MCF-7 cell line. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of non-acidic 4-methylbenzenesulfonate-based ALR2 inhibitors were designed. • Molecular docking was utilized for virtual screening to identify suitable candidates. • Seventeen new compounds were chosen for synthesis and biological evaluation. • In vivo studies were conducted for the most active compound 10a to assess the efficacy. Design and virtual screening of a set of non-acidic 4-methyl-4-phenyl-benzenesulfonate-based aldose reductase 2 inhibitors had been developed followed by chemical synthesis. Based on the results, the synthesized compounds 2 , 4a , b , 7a-c , 9a-c , 10a-c , 11b , c and 14a-c inhibited the ALR2 enzymatic activity in a submicromolar range (99.29–417 nM) and among them, the derivatives 2 , 9b , 10a and 14b were able to inhibit ALR2 by IC 50 of 160.40, 165.20, 99.29 and 120.6 nM, respectively. Moreover, kinetic analyses using Lineweaver–Burk plot revealed that the most active candidate 10a inhibited ALR2 potently via a non-competitive mechanism. In vivo studies showed that 10 mg/kg of compound 10a significantly lowered blood glucose levels in alloxan-induced diabetic mice by 46.10 %. Moreover, compound 10a showed no toxicity up to a concentration of 50 mg/kg and had no adverse effects on liver and kidney functions. It significantly increased levels of GSH and SOD while decreasing MDA levels, thereby mitigating oxidative stress associated with diabetes and potentially attenuating diabetic complications. Furthermore, the binding mode of compound 10a was confirmed through MD simulation. Noteworthy, compounds 2 and 14b showed moderate antimicrobial activity against the two fungi Aspergillus fumigatus and Aspergillus niger. Finally, we report the thiazole derivative 10a as a new promising non-acidic aldose reductase inhibitor that may be beneficial in treating diabetic complications. [ABSTRACT FROM AUTHOR]

[Display omitted] • Three series of 4-substituted pyridopyrimidin derivative were synthesized. • The target compounds were screened for their EGFR inhibitory activity. • The most active compounds were screened for their cytotoxicity. • Compound 4b was subjected to cell cycle analysis and apoptotic assay. • A molecular modeling study was achieved. The present study describes the synthesis of three series of 4-substituted pyridopyrimidin derivatives 4a-h, 5a-d. 6a-d, starting from 2-amino-6-(4-methoxyphenyl)-4-(4-(substituted) phenyl)nicotinonitrile 2a-d via the reaction with N , N -dimethyl- N -' substituted phenyl formimidamide to obtain 4a-h or with either phenyl isothiocyanate 1:1 and 1:2 to obtain 5a-d , 6a-d respectively. The synthesized compounds were evaluated for their effectiveness as EGFR inhibitors against Gefitinib. Six compounds; 4b,g,h, 5c and 6a,d prompted significantly higher EGFR inhibitory activity relative to that of Gefitinib. While two compounds 4d and 4f showed IC 50 values non-significantly different from that of the reference drug. Furthermore, compounds 4a, 4 h, 6a and 6d were chosen to be assessed in vitro for their cytotoxicity against two EGFR -overexpressing cell lines; two human cancer cell lines namely: MCF7 and MDA-MB - 361. Moreover, cell cycle analysis and apoptotic assay was applied for compound 4b that showed most potent inhibitory activity on EGFR, and the highest cytotoxicity against MCF7 and MDA-MB-361, where cell cycle arrest was achieved at pre G and S phases with increased apoptosis. Additionally, a molecular docking study was achieved to inspect the interaction of this compound with the active site of EGFR-TK. [ABSTRACT FROM AUTHOR]

A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended by lipophilic un/substituted phenyl moieties. • New series of thiazole and thiadiazole derivatives were synthesized as SLC-0111 congeners. • Inhibitory activities of such analogues were evaluated towards hCA I, II, IX and XII isoforms. • Compounds 11c and 12b–d showed superior inhibitory activity against hCA IX than SLC-0111. • 11a , 12a , 12b and 12d were found to be selective towards hCAIX and XII over hCA II. • A docking study was done for 12d within the hCA IX active site to justify its inhibitory activity. In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a–d , 12a–d , 16a–c and 17a–d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO 2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a–d and 12a–d) in variable degrees with the following K I ranges: 162.6–7136 nM for hCA I, 9.0–833.6 nM for hCA II, 7.9–153.0 nM for hCA IX, and 9.4–94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (K I s = 8.3 and 7.9 nM, respectively) than SLC-0111 (K I = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity. [ABSTRACT FROM AUTHOR]

[Display omitted] Rational of the design based on duail-tail approach resulting compound 4g with promising biological activity with detailed molecular simulations to justify this activity. • Arylidine-extended pyrazole benzenesulfonamides were designed based on tail approach. • In vitro evaluation for the synthesized compounds took place against hCA I, II, IV and IX. • Compounds 4g and 8a were tested for their cytotoxic activities against MCF-7 and MBA-MB231. • Compound 4g were subjected to cell cycle and apoptotic studies. • Molecular modeling simulations were performed for compounds 4g and 8a to assess their mechanism of action. Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: K I = 71.2 nM, hCAXII: K I = 22.5 nM), (hCAIX: K I = 34.3 nM, hCAXII: K I = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC 50 = 4.15 µM under hypoxic conditions and IC 50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC 50 = 4.34 µM), and hypoxic, (IC 50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds – as representative examples- based on the designed rational. [ABSTRACT FROM AUTHOR]