Nitroimidazole derivatives potentiated against tumor hypoxia: Design, synthesis, antitumor activity, molecular docking study, and QSAR study.

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure-activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b-23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half-maximal inhibitory concentration [IC50 ] = 12.50-24.39 µM) and hypoxic conditions (IC50 = 4.69-11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21-23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ-radiation (IC50 = 2.23-5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin-dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95.

Synthesis, in vitro, and in silico studies of new derivatives of diphenylpiperazine scaffold: A key substructure for MAO inhibition.

Fifteen new diphenylpiperazine hybrids were designed, synthesized and in vitro biologically evaluated against hMAOs enzymes via fluorometric method. All of our new compounds displayed strong inhibitory activities against both two isoforms of hMAOs with IC50 range of 0.091-16.32 µM. According to selectivity index values, all hybrids showed higher selectivity against hMAO-A over hMAO-B. Compound 8 exhibited the best hMAO-A inhibition activity (IC50 value = 91 nM, SI = 19.55). With a selectivity index of 31.02 folds over MAO-B, compound 7 was revealed to be the most effective hMAO-A inhibitor. In silico prediction of physicochemical parameters and BBB permeability proved that all of the newly synthesized compounds have favorable pharmacokinetic profiles and acceptable ADME properties and can pass BBB. For clarification and explanation of the biological activity of compounds 7 and 8, molecular docking simulations were carried out. In light of this, 1,4-diphenylpiperazine analogues can be seen as an encouraging lead to develop safe and effective new drugs for treatment of many disorders such as anxiety and depression by inhibition of hMAO-A enzyme.

Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study.

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds 5c and 5d exhibited the most desirable multiple functions for AD; they were strong hAChE inhibitors with IC50 values of 0.44 and 0.25 µM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC50 = 0.08 and 0.14 µM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aß aggregation and decreasing Aß-related neurodegeneration, especially compound 5d, which was 8 times more effective than curcumin with IC50 = 0.74 µM and 76% inhibition at 10 µM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC50 = 0.38 and 0.44 µM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC50 = 5.15 and 2.42 µM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe+2, Zn+2, and Cu+2, inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD.

Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors.

Synthesis of a new series of 20 compounds bearing the thieno[2,3-d]pyrimidine-4-one scaffold was achieved. The inhibitory activity of these compounds was performed over 60 cell lines of human tumor at single and five dose concentrations. Compounds 20, 22, and 23 exhibited potent growth inhibitions toward the majority of the tested NCI 60 cell lines. Compounds 20 and 23 were the most active compounds with (MG-MID) TGI, GI50, and LC50 values of 16.2, 3.3, 50.1 and 67.7, 6.6, 100, respectively. Also, both compounds showed 7- and 4-fold better activity, respectively, than the standard antitumor agent 5-fluorouracil. Therefore, compounds 20 and 23 were selected to measure their ability to inhibit the dihydrofolate reductase enzyme (DHFR) in comparison to methotrexate (MTX) as a reference drug. Compound 20 was a more potent inhibitor of DHFR (IC50 = 0.20 µM) than MTX (IC50 = 0.22 µM). Molecular modeling studies were performed in the DHFR active site, and it showed compatibility with the results obtained from biological studies. Finally, the results showed that compound 20 is a strong antitumor agent and potent inhibitor of DHFR. In addition, this compound induced cell-cycle arrest in SNB-75 cells in the G2/M phase and the apoptosis process in the Pre-G phase. Compound 20 also increased the level of both caspases-3 and 9 by 11.8- and 50.3-fold, respectively.

Biphenylpiperazine Based MAO Inhibitors: Synthesis, Biological Evaluation, Reversibility and Molecular Modeling Studies.

In this study, 21 new 1,4-biphenylpiperazine derivatives were designed, synthesized and evaluated as monoamine oxidase (MAO) inhibitors by in vitro fluorometric method. All these compounds exhibited inhibitory activity against hMAO enzymes, 17 analogues of them showed selectivity towards hMAO-B over hMAO-A enzyme. Compound 20 exhibited the best activity and selectivity towards hMAO-B with IC50 value of 53 nM and selectivity index of 1122 folds over MAO-A, compared to the reference drugs rasagiline (IC50 = 66 nM) and selegiline (IC50 = 40 nM). Kinetic study and reversibility test of the most potent compound (20) revealed that it is reversible and mixed competitive inhibitor (Ki value is 17 nM for the inhibition of hMAO-B). Compound 20 was evaluated against normal NIH/3T3 mouse embryonic fibroblast cell lines and it was found that it is non-cytotoxic at its effective concentration against hMAO-B. Moreover, compound 20 and the most potent compounds have acceptable ADME properties and good pharmacokinetics profiles. Molecular docking simulations were performed for explanation and elucidation for the biological activity of compounds 19 and 20. Accordingly, 1,4- biphenylpiperazine derivatives can be considered as a promising lead to produce more potent and safer MAO inhibitors for management of various neurological disorders.

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition.

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 µM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 µM, respectively) compared with celecoxib (IC50=6.44 µM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 µM, respectively) comparable to that of celecoxib (IC50=0.68 µM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 µM, respectively) compared with the reference drug roflumilast (IC50=1.55 µM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

Dihydrofolate reductase inhibition effect of 5-substituted pyrido[2,3-d]pyrimidines: Synthesis, antitumor activity and molecular modeling study.

A new series of pyrido[2,3-d]pyrimidines 3-18 bearing substitution at C-5 position was synthesized. All compounds were tested for their in vitro antitumor activity against five human cancer cell lines namely; hepatocellular carcinoma (HePG2), breast carcinoma (MCF-7), human prostate carcinoma (PC3), colorectal carcinoma (HCT-116), and cervical carcinoma (Hela) using doxorubicin as a positive control. Compounds 3, 4, 9, 11, 13, 14, 15 and 17 exhibited the highest antitumor activity against the tested cell lines and were selected to screen their enzymatic inhibition against dihydrofolate reductase enzyme (DHFR) compared with the reference drug methotrexate (MTX), to explain the probable mechanism of action of the observed anticancer activity. Compound 11 displayed the highest inhibitory activity (IC50 = 6.5 µM) among the tested compounds in comparison with MTX (IC50 = 5.57 µM). Also, compounds 13 and 14 showed high inhibitory activity against DHFR with IC50 values 7.1 and 8.7 µM, respectively. Comparative molecular modeling study was performed between DHFR inhibitors 11, 13 and 14 of the highest activity and 10 of the lowest activity among the eight inhibitors against MTX. Docking studies into the active site of DHFR domain showed good agreement with the obtained biological results. Finally, compound 11 was found to be best antitumor, DHFR inhibitor, and it induced the process of apoptosis at Pre-G phase and cell cycle arrest at G2/M phase in MCF-7 cells.

Structural alterations based on naproxen scaffold: Synthesis, evaluation of antitumor activity and COX-2 inhibition, and molecular docking.

A new series of non-carboxylic naproxen analogues, bearing a variety of ring systems, such as oxadiazoles 3a-c and 6a-c, cycloalkanes 4a-d, cyclic imides 5a-c, and triazoles 7-9 and 10a-c, was synthesized. In addition, in vitro antitumor activity and cyclooxygenase isozymes (COX-1/COX-2) inhibition assay of the target compounds 3-10 was studied. The results of the antitumor activity assays indicated that compounds 4b, 6c, 10b, and 10c exhibited the greatest antitumor activities against the tested cell lines MCF-7, MDA-231, HeLa, and HCT-116, with an IC50 range of 4.83-14.49 µM. By comparison, the reference drugs doxorubicin, afatinib, and celecoxib yielded IC50 values of 3.18-26.79, 6.20-11.40, and 22.79-42.74 µM, respectively. Furthermore, in vitro COX-1/COX-2 inhibition testing showed that the compounds 4b, 6c, 10b, and 10c exhibited effective COX-2 inhibition, with IC50 values of 0.40-1.20 µM, and selectivity index (SI) values of >62.50-20.83, using celecoxib as a reference drug (IC50 = 0.11 µM; COX-2 SI: >227.20). Compounds 6c and 10c, which were potent COX-2 inhibitors, were docked into the COX-2 binding site, where these compounds exhibited strong interactions.

Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies.

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC50 = ∼0.20-0.69 µM), with SI values of (>72.5-250) compared with celecoxib (IC50 = 0.16 µM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50 > 50 µM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 µM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition = ∼0-10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.

Design, synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors.

A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner.

Synthesis, antitumour and antioxidant activities of novel α,ß-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

New α,ß-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC50] ≅5.5-18.1 µΜ), in addition to significantly high ABTS•+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC50 values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC50 values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC50 = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study.

A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b-9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b-9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC50 range of 7.7-14.2 µg/ml, in comparison with the reference drugs 5-fluorouracil (IC50 = 7.9 and 5.3 µg/ml, respectively) and afatinib (IC50 = 5.4 and 11.4 µg/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC50 values at micromolar levels (IC50 range of 16.01-1.11 µM) compared with the reference drugs sorafenib (IC50 = 1.14 µM) and erlotinib (IC50 = 0.1 µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase.