New thiazole-based derivatives as EGFR/HER2 and DHFR inhibitors: Synthesis, molecular modeling simulations and anticancer activity.

New series of thiazole and imidazo[2,1-b]thiazole derivatives were synthesized and tested for their in vitro anticancer activity. Compounds 27, 34, 39 and 42-44 showed the best anticancer activity against the tested cancer cell lines with high safety profile and selectivity indices, especially MCF-7 breast cancer, compared to sorafenib. As an attempt to reveal their mode of cytotoxicity, EGFR, HER2 kinase and DHFR inhibition assays were performed. Compounds 39 and 43 were the most potent dual EGFR/HER2 kinase inhibitors, with IC50 values of 0.153 (EGFR), 0.108 (HER2) and 0.122 (EGFR), 0.078 (HER2) µM, respectively. 39 and 42 were the best DHFR inhibitors showing IC50 0.291 and 0.123 µM, respectively. 39 and 43 induced their cytotoxicity via cell cycle arrest at G1/S and G1 phases, respectively, and apoptosis rather than necrosis in the MCF-7 breast cancer cell line. In vivo anti-breast cancer assay of 39 and 43 showed significant tumor volume reduction with recovered caspase-3 immunoexpression. Modeling study results proved the importance of the 5-(4-substituted phenyl)-imidazo[2,1-b]thiazole moiety and the hydrazide side chain for the anticancer activity. The most potent compounds showed good drug-likeness features and could be used as prototypes for further optimization. 39 could be an example of a multi-targeting anticancer agent that acts by inhibiting EGFR/HER2 kinase, DHFR enzymes and cellular apoptosis.

Synthesis and Biological Evaluation of Thiazole-Based Derivatives as Potential Acetylcholinesterase Inhibitors.

Nineteen new thiazole-based derivatives were synthesized and their structures characterized with analytical and spectral data. The in vitro assessment of their acetylcholinesterase (AChE) inhibitory activity revealed that compounds 10 and 16 produced potent AChE inhibitory activities with IC50 values of 103.24 and 108.94 nM, respectively. Compounds 13, 17, 18, 21, 23, 31, and 33 displayed moderate activity with 25-50% relative potency compared to the known potent AChE inhibitor donepezil. Molecular docking studies of the active compounds docked within the active site cavity of AChE showed a binding orientation similar to that of donepezil, with good predicted binding affinities. These compounds could therefore be considered as potential lead compounds for the development of new and potentially improved AChE inhibitors.

Cyclohepta[b]thiophenes as Potential Antiproliferative Agents: Design, Synthesis, In Vitro, and In Vivo Anticancer Evaluation.

Several thiophene featuring compounds are known for their promising antiproliferative activity. Prompted by the urgent need to identify new potent anticancer agents, 16 compounds of benzamides, benzylamines, and urea analogues incorporating a cyclohepta[b]thiophene scaffold were synthesized and biologically evaluated with a cell proliferation assay using the A549 nonsmall cell lung cancer cell line. Compound 17 demonstrated both potent and broad-spectrum anticancer activity with submicromolar 50% growth inhibition (GI50) values. It also showed superior antiproliferative activity (vs nocodazole) in OVACAR-4, OVACAR-5, CAKI-1, and T47D cell lines with GI50 values of 2.01 (vs 22.28), 2.27 (vs 20.75), 0.69 (vs 1.11), and 0.362 (vs 81.283) µM, respectively. Additionally, compound 17 displayed minimal cytotoxicity based on 50% lethal concentration (LC50) values toward all tested cell lines. Further cell-based mechanistic studies of compound 17 revealed its ability to induce cell cycle arrest of A549 cells as evidenced by dose dependent G2/M accumulation. Furthermore, induction of early apoptosis along with activation of caspase 3, 8, and 9 were confirmed in A549 cells treated with compound 17. Targeting tubulin polymerization may explain the mechanism of the antiproliferative activity of compound 17 based on cell cycle analysis, detected apoptosis, and in vitro inhibition of tubulin polymerization. In vitro data were further supported by in vivo antitumor efficacy studies of compound 17 in a CT26 murine model for which the results showed a reduction in the tumor growth compared to untreated mice. Overall, compound 17 has the potential to function as a promising candidate for further development of potent anticancer chemotherapeutics.

Synthesis of Cyclobutane Analogue 4: Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives.

The coupling of 2-bromo-3-benzoyloxycyclobutanone with purine under basic conditions produces two regioisomers consisting of the N-7 and N-9 alkylated products in equal amounts in their racemic forms. The distribution of the isomers is consistent with the charge delocalization between the N-7 and N-9 positions of the purinyl anion. The structural assignments and relative stereochemistry of each regioisomer were based on 1 and 2D NMR techniques. The relative stereochemistry of the C-2 and C-3 substituents in each regioisomer was the trans orientation consistent with steric factors in the coupling step. The N-9 regioisomer was reduced with sodium borohydride to give the all trans cyclobutanol as the major product in a stereoselective manner. The alcohol was debenzoylated with sodium methoxide in a transesterification step to give the nucleoside analogue. The regioisomeric pyrimidine nucleosides were prepared by Vorbrüggen coupling of the 3-hydroxymethylcyclobutanone triflate with either thymine or uracil followed by stereoselective hydride addition. Regiospecificity of the coupling at the N-1 position was observed and stereoselective reduction to the trans-disubstituted cyclobutanol structure assignments was based on NMR data.

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies.

Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32 µg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies.

The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63-3.09 µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI50; 22.60 µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 µM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2.

A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0 µM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1 µM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4 mg/kg) relative to diclofenac (ED50=114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95 Å), Phe(518)(2.82 Å) and Arg(513)(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis and evaluation of some novel quinazolinone derivatives as diuretic agents.

A new series of quinazolin-4(3H)-one derivatives containing either a thiazole or a 1, 3, 4-thiadiazole moiety were prepared in order to study the effect of such a heterocyclic combination on the expected diuretic activity. Synthesis of the target compounds (2, 4, and 6) has been achieved through an interaction of the starting 7-chloro-2-methyl-4H-3, 1-benzoxazin-4-one 1 with different heterocyclic amines. Alkylation of 3-(2-mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivative 4 with different alkyl halides or chloroacetic acid afforded the corresponding thioethers 5 while interaction of 2-methyl-3-(1, 3, 4-thiadiazol-5-yl or thiazol-5-yl)quinazolin-4(3H)-ones (2 and 6) with various aromatic aldehydes resulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the other hand, 2-morpholinomethyl-3-(2-sulfamoyl or mercapto-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one derivatives 10 have also been synthesized through an interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Biological evaluation of some of the target compounds as diuretic agents was carried out. The results showed that 2-[2-(4-chlorophenyl)vinyl]-7-chloro-3-(2-sulfamoyl-1, 3, 4-thiadiazol-5-yl)quinazolin-4(3H)-one 7b exhibited significant diuretic activity. The detailed synthesis, spectroscopic and biological data are reported.

Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives.

Synthesis of some new derivatives of 2-aryl-4-oxo-1-(4-quinazolyl)quinazolines is described. Methyl N-(4-quinazolyl)anthranilate was allowed to react with phenyl iso(thio)cyanate to give 3-phenyl-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydro-2, 4-dioxo- and 4-oxo-2-thioxoquinazolines (3a and 3b respectively) Alternatively, anthranilic acid amide derivatives were subjected to cyclization with aromatic aldehydes to give 2-aryl-4-oxo-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydroquinazolines 5. On the other hand, 2-chloro-4-(4-substituted 1-piperazinyl)quinazoline derivatives were subjected to the same type of reactions at the 2-position to afford the corresponding quinazoline derivatives 8 and 10 respectively. Furthermore, the acid amide 4b cyclized with acid chlorides to give the corresponding 2-aryl-1-(2-chloro-4-quinazolyl)-4-oxo-1, 4-dihydroquinazolines 11 from which the triazoloquinazoline derivatives 13 and 15 were synthesized through the intermediate hydrazine derivatives 12. Most of the newly synthesized compounds were tested for their antiinflammatory activities. However, some of the novel compounds were found to exhibit good antiinflammatory potencies.