Design,synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine and quinazoline derivatives as potent antitumor agents

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC₅₀ values of 1.78 μM, 1.02 μM, 1.98 μM, 0.41 μM and 0.22 μM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC₅₀ value of 0.20 μM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno[3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno[3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity.     

Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC₅₀ = 58.43 μM) as well as for SIRT2 (IC₅₀ = 45.12 μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure–activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.     

Synthesis and antitumor activity of amine analogs of irofulven

Acylfulvenes, a class of semisynthetic analogs of Illudin S, show high toxicity toward prostate cancer cells. Here we probe the effect of changes in hydrophilic character of the analogs.     

Synthesis,in vitro and in vivo antitumor and antiviral activity of novel 1-substituted benzimidazole derivatives

Abstract

A novel series of 5-nitro-1H-benzimidazole derivatives substituted at position 1 by heterocyclic rings was synthesized. Cytotoxicity and antiviral activity of the new compounds were tested. Compound 3 was more active than doxorubicin against A-549, HCT-116 and MCF-7. However, compound 3 showed no activity against human liver carcinoma Hep G-2 cell line. Compounds 9 and 17b (E) showed potency near to doxorubicin against the four cell lines. The acute toxicity of compound 9 on liver cancer induced in rats was determined in vivo. Interestingly, it showed restoration activity of liver function and pathology towards normal as compared to the cancer-bearing rats induced by DENA. Compounds 17a (Z), 17b (E) and 18a (Z) were the most promising compounds for their antiviral activity against rotavirus Wa strain.     

Synthesis and biological evaluation of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

A series of novel alkyl amide functionalized trifluoromethyl substituted pyrazolo[3,4-b]pyridine derivatives 5, 6 and 7 were prepared starting from 6-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 3 via selective N-alkylation, followed by reaction with different primary aliphatic amines, cyclic secondary amines or l-amino acids under different set of conditions. All the synthesized compounds 5, 6 and 7 were screened for anticancer activity against four cancer cell lines such as A549—Lung cancer (CCL-185), MCF7—Breast cancer (HTB-22), DU145—Prostate cancer (HTB-81) and HeLa—Cervical cancer (CCL-2). The compounds 5i and 6e are found to have promising bioactivity at micro molar concentration.     

Synthesis of phenanthroindolizidine alkaloids and evaluation of their antitumor activities and toxicities

We previously reported that phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem. To address this problem, new phenanthroindolizidine derivatives were synthesized and their antitumor activities and toxicities were evaluated. This study describes the relationship between the chemical structures, antitumor activities, and toxicities of these phenanthroindolizidine derivatives. Based on its properties, compound 8 was found to be the most suitable potential antitumor agent.     

Synthesis and antitumor evaluation of benzopsoralen analogues

The synthesis of five new tetracyclic benzopsoralen analogues, compounds 2-6, with 9H-xanthen-9-one or 9H-carbazole frameworks, is described. Their inhibitory effects on the growth of three human tumor cell lines (MCF-7, SF-268, and NCI-460) were evaluated, and discussed in terms of structure-activity relationship, taking into account both geometric and electronic features. Generally, the angular compounds showed significant biological activities, but the arrangement of functional groups also contributed to the overall activity.     

Synthesis of benzensulfonamides linked to quinazoline scaffolds as novel carbonic anhydrase inhibitors

Carbonic anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10–29, 31, 32, 35, 36, and 45–51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14, 15, 17, 19, 20, 21, 24, 25, 28, 29, 31, 35, 45, 47, 49, and 51 with inhibition constant (K_Is) values of 39.4–354.7 nM that were nearly equivalent or even greater than that of AAZ (K_I, 250.0 nM). Compounds 15, 20, 24, 28, 29, 45 and 47 proved to have inhibitory activities against hCA II with (K_Is, 0.73–16.5 nM) that were similar or improved to that of AAZ (K_I, 12.0 nM). Compounds 13–29, 31–32, and 45–51 displayed potent hCA IX inhibitory activities (K_Is, 1.6–32.2 nM) that were more effective than or nearly equal to AAZ (K_I, 25.0 nM). Compounds 14, 15, 20, 21, 26, 45, and 47 exerted potent hCA XII inhibitory activities (K_Is, 5.2–9.2 nM), indicating similar CAI activities as compared to that of AAZ (K_I, 5.7 nM).     

Synthesis,characterization and in vitro,in vivo,in silico biological evaluations of substituted benzimidazole derivatives

A series of substituted benzimidazole derivatives were synthesized by reacting O-phenylenediamine with various aromatic aldehydes or glycolic acid using various inexpensive reagents in aqueous media. Synthesized compounds were characterized and elucidated by IR, ¹H NMR, ESI-MS spectra. Resultant compounds were screened for in vitro antimicrobial, cytotoxic, antioxidant, lipid peroxidation and cholinesterase inhibitory activities, in vivo analgesic and anti-inflammatory, and in silico anti-acetylcholinesterase and anti-butyrylcholinesterase activities. Among the synthesized compounds, compound 3b showed most promising central analgesic effect (46.15%) compared to morphine (48.08%), whereas compounds 6, 3c and 3a showed significant peripheral analgesic activity at two different dose levels (25 mg/kg and 50 mg/kg). Compounds 3b and 3a at the dose of 100 mg/kg showed significant anti-inflammatory effects from the first hour and onward, whereas compounds 6 and 3b showed moderate cytotoxic activities. In addition, compound 3a showed significant antioxidant activity having IC₅₀ value of 16.73 µg/ml compared to 14.44 µg/ml for the standard BHT. Compound 6, 3a and 3b exhibited mild to moderate cholinesterase inhibitory activity. In silico studies revealed that compound 3a and 3b might be suitable for cholinesterase inhibitory activity. A comprehensive computational and experimental data suggested compounds 3b and 3a as the best possible candidates for pharmacological activity. All the experimental data were statistically significant (p < 0.01 level).     

Synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential atypical antipsychotics

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.     

Synthesis,in vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives

Protein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as a promising target in anticancer therapy. New derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) bearing azide or substituted triazole groups were synthesized. Their influence on the activity of human recombinant CK2α and cytotoxicity against normal and cancer cell lines were evaluated. TBBi derivatives with triazole substituted with carboxyl substituent (7 and 10) exhibited the most potent inhibitory activity against CK2 with K_i value in the range of 1.96–0.91 μM, respectively. New TBBi derivatives 2, 3, 5 and 9 have demonstrated the EC₅₀, in the range of 12–25 μM and 13–29 μM respectively towards CCRF-CEM and MCF-7 cells. Derivatives TBBi decreased viability of cancer cells more efficiently than BALB cells and the biggest differences were observed for the azide substituted compounds 3 and 5. The effect of the most active compounds on the activity of eight off-target kinases was evaluated. Inhibitory efficiency of CK2-mediated p65 phosphorylation was demonstrated for the TBBi and compound 12.     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Synthesis of novel psoralen analogues and their in vitro antitumor activity

New tetracyclic benzofurocoumarin (benzopsoralen) analogues were synthesized and their inhibitory effect on the growth of tumor cell lines was evaluated. The human tumor cell lines used were MDA MB231 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and TCC-SUP (bladder transitional cell carcinoma). The in vitro antitumor activity of the new benzopsoralens was discussed in terms of structure–activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds in order to evaluate the potential of these compounds to interact with the heme group of the enzymes. The results have demonstrated that the linear compounds have the most pronounced activity against tumor cell lines and this might be related to the better accessibility that these compounds have to the active site in relation to the angular ones that have shown in the majority of the cases multiple binding poses in the active site of CYP2A6.     

Synthesis,antitumor activity and DNA binding features of benzothiazolyl and benzimidazolyl substituted isoindolines

In this paper novel isoindolines substituted with cyano and amidino benzimidazoles and benzothiazoles were synthesized as new potential anti-cancer agents. The new structures were evaluated for antiproliferative activity, cell cycle changes, cell death, as well as DNA binding and topoisomerase inhibition properties on selected compounds. Results showed that all tested compounds exerted antitumor activity, especially amidinobenzothiazole and amidinobenzimidazole substituted isoindolin-1-ones and benzimidazole substituted 1-iminoisoindoline that showed antiproliferative effect in the submicromolar range. Moreover, the DNA-binding properties of selected compounds were evaluated by biophysical and biochemical approaches including thermal denaturation studies, circular dichroism spectra analyses and topoisomerase I/II inhibition assays and results identified some of them as strong DNA ligands, harboring or not additional topoisomerase II inhibition and able to locate in the nucleus as determined by fluorescence microscopy. In conclusion, we evidenced novel cyano- and amidino-substituted isoindolines coupled with benzimidazoles and benzothiazoles as topoisomerase inhibitors and/or DNA binding compounds with potent antitumor activities.     

Synthesis and antitumor activity of new retinobenzoic acids

New retinobenzoic acid derivatives have been synthesized starting from 1,2,3,4-tetrahydro-1,1,2,4,4,6-hexamethylnaphthalene and 1,1,2,3,3-pentamethylindane. Four of the synthetic compounds displayed potent cytotoxic activities in vitro against human breast cancer and leukemic cell lines. Thus, these molecules can be further evaluated for the treatment of human leukemia and breast cancer.     

Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2

Both c-Met and VEGFR-2 are important targets for the treatment of cancers. In this study, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinazolin-4-amine derivatives were designed and identified as dual c-Met and VEGFR-2 inhibitors. Among these compounds bearing quinazoline and benzimidazole fragments, compound 7j exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC₅₀ of 0.05 μM and 0.02 μM, respectively. It also showed the highest anticancer activity against the tested cancer cell lines with IC₅₀ of 1.5 μM against MCF-7 and 8.7 μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, which demonstrates that compound 7j is a potential agent for cancer therapy deserving further researching.     

Exploration of in vitro time point quantitative evaluation of newly synthesized benzimidazole and benzothiazole derivatives as potential antibacterial agents

Present communication deals with the in vitro time point quantitative antibacterial evaluation of newly synthesized 1,2-disubstituted benzimidazoles (3a–p) and 2-substituted benzothiazoles (5a–h) against Gram-positive bacteria Staphylococcus aureus, Bacillus cereus, and Gram-negative bacteria Vibrio cholerae, Shigella dysenteriae and Escherichia coli. These compounds were synthesized under mild reaction conditions using Al₂O₃–Fe₂O₃ nanocrystals as heterogeneous catalyst. Bio-evaluation studies revealed that, compounds 3a, 5a and 5d exhibited moderate to good antibacterial activity against all the tested bacterial stains. The compounds 3a, 3f and 5a have shown enhanced inhibitory activity compared with standard antibacterial drug ciprofloxacin against V. cholerae, B. cereus, and S. dysenteriae, respectively. Additionally, the compounds 3a, 3e, 3f, 3h and 5b displayed complete bactericidal activity within 24 h, whereas ciprofloxacin took 48 h to kill those bacteria completely.     

Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.     

Synthesis and evaluation of in vitro antioxidant capacities of some benzimidazole derivatives

New, except 1d, melatonin analogue benzimidazole derivatives were synthesized and characterized in the present study. The potential role of melatonin as an antioxidant by scavenging and detoxifying ROS raised the possibility that compounds that are analogous to melatonin can also be used for their antioxidant properties. Therefore the antioxidant effects of the newly synthesized compounds were investigated in vitro by means of their inhibitory effect on hydrogen peroxide-induced erythrocyte membrane lipid peroxidation (EMLP) and on various erythrocyte antioxidant enzymes viz. superoxide dismutase (SOD), catalase (CAT) and glucose-6-phosphate dehydrogenase (G6PD). The synthesized benzimidazole derivatives showed remarkable antioxidant activity in vitro in the H₂O₂-induced EMLP system. Furthermore their effects on various antioxidant enzymes are discussed and evaluated from the perspective of structure- activity relationships.