Virtual screening approach for the discovery of selective 5α-reductase type II inhibitors for benign prostatic hyperplasia treatment.

Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.

Development of pyrolo[2,3-c]pyrazole, pyrolo[2,3-d]pyrimidine and their bioisosteres as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological evaluation and molecular dynamics investigations.

Inhibiting the CDK2/cyclin A2 enzyme has been validated in multiple clinical manifestations related to multiple types of cancer. Herein, novel series of pyrolo[2,3-c]pyrazole, pyrolo[2,3-c]isoaxazole and pyrolo[2,3-d]pyrimidine, pyrolo[3,2-c]pyridine & indole based analogs were designed, synthesized and biologically evaluated for their in vitro antiproliferative activity where the obtained results revealed that most of the newly synthesized compounds showed significant cytotoxic activity towards MCF-7 (breast cancer cell lines) and HepG-2 (hepatocellular carcinoma) with IC50 ranging from 3.20 µM to 10.05 µM & from 2.18 µM to 13.49 µM, respectively, compared to that of Sorafenib (IC50 9.76 & 13.19 µM, respectively). The in vitro inhibitory profile of the most promising compounds (9, 11, 14, 15, 16, 17 and 20) towards CDK2/CyclinA2 was evaluated. Compounds 14 & 15 exhibited potent inhibitory profile against CDK2 with (IC50 0.11 and 0.262 µM, respectively comparable to Sorafenib IC50 0.184 µM. Western blotting of 14 & 15 at MCF-7 cell line confirmed the diminishing activity on CDK2. Furthermore, both compounds exserted a significant cell cycle arrest and apoptosis. Moreover, the normal cell line cytotoxicity for both compounds revealed low cytotoxic results in normal cells rather than cancer cells. Molecular docking and dynamic simulation validated the potentiality of the newly synthesized compounds to have high binding affinity within CDK2 binding pocket. 3DQSAR pharmacophore, in-silico ADME/TOPKAT studies and drug-likeness showed proper pharmacokinetic properties and helped in structure requirements prediction. The obtained model and pattern of substitution could be used for further development of CDK2 inhibitors.

Synthesis, biological evaluation, and in silico studies of new CDK2 inhibitors based on pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold with apoptotic activity.

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

Design, synthesis, docking study and anticancer evaluation of new trimethoxyphenyl pyridine derivatives as tubulin inhibitors and apoptosis inducers.

Microtubules have become an appealing target for anticancer drug development including mainly colchicine binding site inhibitors (CBSIs). A new series of novel trimethoxypyridine derivatives were designed and synthesized as tubulin targeting agents. In vitro anti-proliferative activities of the tested compounds compared to colchicine against hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7) was carried out. Most of compounds showed significant cytotoxic activities. Compounds Vb, Vc, Vf, Vj and VI showed superior anti-proliferative activities to colchicine. Where compound VI showed IC50 values of 4.83, 3.25 and 6.11 µM compared to colchicine (7.40, 9.32, 10.41 µM) against HCT 116, HepG-2 and MCF-7, respectively. The enzymatic activity against tubulin enzyme was carried out for the compounds that showed high anti-proliferative activity. Also, compound VI exhibited the highest tubulin polymerization inhibitory effect with an IC50 value of 8.92 nM compared to colchicine (IC50 value = 9.85 nM). Compounds Vb, Vc, Vf, Vj, & VIIIb showed promising activities with IC50 values of 22.41, 17.64, 20.39, 10.75, 31.86 nM, respectively. Cell cycle and apoptosis test for compound VI against HepG-2 cells, indicated that compound VI can arrest cell cycle at G2/M phase, and can cause apoptosis at pre-G1 phase, with high apoptotic effect 18.53%. Molecular docking studies of the designed compounds confirmed the essential hydrogen bonding with CYS241 beside the hydrophobic interaction at the binding site compared to reference compounds which assisted in the prediction of the structure requirements for the detected antitumor activity.

Design, synthesis and molecular modeling study for some new 2-substituted benzimidazoles as dual inhibitors for VEGFR-2 and c-Met.

AIM: Computer-aided drug design techniques were adopted to design three series of 2-substituted-5-nitrobenzimidazole derivatives hybridized with piperzine 5a,b, oxadiazole 7a,b, 9, 14a-c and triazolo-thiadiazole moieties 12a-d, as VEGFR-2/c-Met kinase inhibitors. MATERIALS & METHODS: The designed compounds were synthesized adopting the chemical pathways outlined in schemes 1 and 2 to afford the desired three series followed by evaluating their inhibitory activities against VEGFR-2 and c-Met and in vitro anticancer activities. RESULT: Analogs bearing substituted phenyl ring attached to oxadiazole ring 14a showed the greatest inhibitory activities against non-small-cell lung cancer NCI-H522 and melanoma SK-MEL-2 with inhibition percent of 48.70 and 42.62, respectively. Moreover, unsubstituted phenoxymethyl derivative 12d exhibited promising inhibitory activity against VEGFR-2 and c-Met (35.88 and 88.48%), respectively. CONCLUSION: The above results revealed that 2-substituted-5-nitrobenzimidazole hybridized with various heterocyclic scaffolds could be a potential anticancer agent.

Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives.

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 µM ranging from 0.495 to 5.57 µM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 µM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer.

Anticancer and radiosensitizing evaluation of some new pyranothiazole-Schiff bases bearing the biologically active sulfonamide moiety.

The present work reports the synthesis of some new Schiff bases, 5-(substituted benzylideneamino)-6-cyano-7H-7-(4-methoxyphenyl)-2-(4-sulphamoylphenylamino) pyrano[2,3-d]thiazole (5-15). The design of the structures of these compounds complies with the general pharmacophoric requirements for CA inhibiting anticancer drugs. The newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed interesting cytotoxic activities compared to doxorubicin as a reference drug. Compounds 4, 6-8 and 11 (IC(50): 27.51, 10.25, 9.55, 9.39 and 9.70 µM, respectively) exhibited higher cytotoxic activities than the reference drug doxorubicin (IC(50): 32.00 µM). Additionally, the previously mentioned compounds were evaluated again for their ability to enhance the cell killing effect of γ-radiation.

Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives.

In an effort to establish new candidates with improved anticancer activity, we report here the synthesis of various series of 2-substituted benzimidazoles: 2-[(4-oxothiazolidin-2-ylidene) methyl and (4-amino-2-thioxothiazol-5-yl) benzimidazoles (2 and 3, respectively); 2-[(4-fluorobenzylidene and cycloalkylidene) cyanomethyl] benzimidazoles (4 and 5, respectively), together with the synthesis of certain of 2-[(4- or 5-oxothiazolidin-2-ylidene, 4-substituted thiazolyl-2-ylidene and [1,3]thiazin-2-ylidene)cyanomethyl]benzimidazoles (6, 8, 7 and 9, respectively). Several of the synthesized products were subjected to in vitro anticancer screening that revealed that all the tested compounds exhibited antitumor activity against human hepatocellular carcinoma (HEPG2), human breast adenocarcinoma (MCF7) and human colon carcinoma (HCT 116) cell lines, with IC50's<10 microg/ml.

Synthesis and anti-inflammatory activity of certain piperazinylthienylpyridazine derivatives.

In this study, a novel series of 2-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (3a-f), 2-(4-substituted piperazin-l-yl carbonylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (4a-c) and 2-[2-(4-substituted piperazin-l-ylcarbonylethyl)]-6-(thien-2-yl)-2H-pyridazin-3-ones (5a,b) were prepared from 6-(thien-2-yl)-2H- pyridazin-3-one (1). In addition, 3-(4-substituted piperazin-l-ylcarbonyl methyl thio)-6-(thien-2-yl) pyridazines (6a-c) and 3-[2-(4-substitutedpiperazin-1-ylcarbonyl ethylthio]-6-(thien-2-yl) pyridazines (7a,b) were synthesized. Furthermore, 5-(4-substituted piperazin-l-ylmethyl)-6-(thien-2-yl)-2H-pyridazin-3-ones (12a,b) were prepared. The structures of the new compounds were confirmed by elemental analysis as well as by 1H-NMR, IR and MS data. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity against carrageenan-induced paw edema at a dose of 10 mg/kg using indomethacin as the reference standard.

Synthesis and antimicrobial activity of certain novel quinoxalines.

In this study, certain 3-methyl-2-[4-(substituted amino carbonyl)anilino] quinoxalines, (2a-d) and (3a-d), were synthesized from the new key compound 2-[4-(ethoxycarbonyl)anilino]-3-methyl quinoxaline (1). In addition, a series of 2-[4-(arylidene hydrazinocarbonyl)anilino]-3-methyl quinoxalines (5a-e), as well as their cyclized oxadiazolinyl derivatives (6a-e), and a series of 2-[4-N2-acylhydrazinocarbonyl) anilino]-3-methyl quinoxalines (7a-d), as well as their cyclized oxadiazoiyl derivatives (8a-d) were also prepared. Some of these derivatives were evaluated for antimicrobial activity in vitro. It was found that all the selected compounds exhibit antimicrobial activity and that compound 5b had a broad spectrum of activity.