Synthesis,biological evaluation,and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents

A series of pyrazolyl-acylhydrazone derivatives (1e–20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC₅₀ values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC₅₀ = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Synthesis, biological evaluation and molecular docking studies of 1,3-benzoxazine derivatives as potential anticancer agents

A series of 6 and/or 8-substituted derivatives of 1,3-benzoxazines, having flavone moiety at 3-position, have been synthesized. For synthesis of the compounds, 6 or/and 8-substituted saliscylaldehydes were reacted with aminoflavone followed by reduction, and CHCl₃/HCHO promoted cyclization to give corresponding aminoflavone precursors which provided the desired 1,3-benzoxazine skeleton. Cytotoxic effects of the synthesized compounds were investigated in vitro against human breast cancer (MCF-7) cell lines. Among the compounds tested, methyl (3f and 6f), methoxy (3h, 3i, and 6h), and chloro (3d) derivatives were found to be most potent with IC₅₀ values of 14.3, 14.9, 17.1, 8.03, 12.1, and 12.03 μM, respectively. Molecular docking studies of most active compounds of the series revealed that they bind to a narrow hydrophobic pocket of the N-terminal chain in the ATP binding site of EGFR.     

Synthesis and evaluation of some novel benzothiazole derivatives as potential anticancer and antimicrobial agents

Intensive efforts are underway worldwide to develop anticancer and antimicrobial agents. Therefore, a novel series of pyrido[2,1-b]benzo [d]thiazole and 2-(benzo [d] thiazol-2-ylamino)pyrimidine derivatives was synthesized. The synthesized compounds were evaluated for their anticancer activity. Among the tested compounds, compounds 3a, 3b, and 7 exhibited more cytotoxic action than the control drug doxorubicin (CAS 23214-92-8; IC50: 52 microg/ml). Compound 7 was the most potent cytotoxic, with an IC50 of 42.55 pg/ ml, while compounds 3a and 3b induced high cytotoxic action with IC50 values of 50.15 pg/ml and 50.45 pg/ml, respectively. Moreover, the synthesized compounds were screened for their antibacterial and antifungal activities. Compound 6 exhibited moderate antifungal activity against C. albicans with a minimum inhibitory concentration of 125 pg/ml.     

Synthesis, antimicrobial evaluation, and docking studies of novel 4-substituted quinazoline derivatives as DNA-gyrase inhibitors

Quinazoline derivatives are reported to have anti‐inflammatory, analgesic, antibacterial, and anticancer activities. The incorporation of “OCH₂CONH₂” (oxymethylcarbamide) at 4^th position of the quinazoline ring was found to influence the biological activities of the molecules. With this rationale, some new oxadiazolyl methyloxy quinazolines, pyrazolyl acetoxy methyl quinazolines, triazolylmethyloxy quinazolines were synthesized from anthranilic acid through quinazolyl oxyacetylhydrazide intermediates. All the compounds were characterized by IR, ¹H‐NMR, EI‐MS, and C, H, N analyses and evaluated for their antimicrobial activity. Docking studies on the DNA‐gyrase enzyme (1KZN) show their role in the antimicrobial activity of the molecules and explain the higher potency of compounds 6a , 6b , 8a , 8b based on ReRanking scores and binding poses of the molecules.     

Synthesis and biological evaluation of novel 4,5-dihydropyrazole derivatives as potent anticancer and antimicrobial agents

A focused library of 4,5-dihydropyrazole dervivatives (4, 5, 6, 7a–h, 8, 9a–g, and 10a–g) were synthesized from novel 5-(2,6-difluorophenyl)-3-phenyl-4,5-dihydropyrazole-1-carbothioamide 4. The synthesized compounds were characterized using elemental analysis and spectral data (IR, mass spectra, ¹H and ¹³C NMR) and evaluated for antimicrobial activity by broth dilution method and in vitro anticancer activity. Among the synthesized compounds 7a, 9c, 9g, and 10d exhibit broad spectrum antimicrobial activity against tested microbial strains. The in vitro cancer results ascertain 7a, 9c, and 10d are most potent molecules in comparison to reference standard cisplatin.     

Synthesis and biological evaluation of novel hydroquinone dimethyl ethers as potential anticancer and antimicrobial agents

The synthesis of two novel series of quinol dimethyl ethers linked to either various functionalities or to some biologically active nitrogenous heterocycles is described. Nine of the newly synthesized quinol dimethyl ethers 5a, b, 9b, 10a, d, 12a, b, and 13a, b were selected by the NCI and were tested initially at a single high dose (10 μM) in the full NCI 60 cell panel. Four of the screened quinol dimethyl ethers bearing unsubstituted phenylhydrazone 5a, 4-chlorophenylhydrazone 5b, 4-chlorophenyl-3-sulfanyl-1,2,4-triazole 9b, as well as 4-chloroanilino-1,3,4-oxadiazole 12b moieties satisfied the threshold antitumor screen. 4-Chlorophenylhydrazone 5b showed very promising results and accordingly was chosen for in vivo antitumor screening. Thus, compound 5b of the series could be considered as the potential lead for development of novel anticancer agents. In addition, compounds 5a–c, 6a–c, 9a–c, 10a, b, d, e, g, h, 11a–c, 12a–c, and 13a–c were screened for their in vitro antimicrobial activity. Some of the tested compounds exhibited special high activity comparable to the reference ampicillin against Pseudomonas aeruginosa and Escherichia coli.     

Synthesis and biological evaluation of some novel fused pyrazolopyrimidines as potential anticancer and antimicrobial agents

Synthesis and evaluation of anticancer and antimicrobial activity of some novel pyrazolopyrimidines and fused pyrazolopyrimidines are reported. Twelve analogs were selected to be evaluated for their in vitro anticancer potential against a panel of three human tumor cell lines: hepatocellular carcinoma HepG2, cervical carcinoma HelaS3 and colon carcinoma CaCo. The obtained data revealed that eight compounds namely; 6b, 6d, 7c, 8c, 10b, 12b, 13a and 13b were able to exhibit variable degrees of anticancer activities against the three used cell lines, of which compound 6d proved to be the most active. On the other hand, all the newly synthesized compounds were subjected to in vitro antibacterial and antifungal screening. Almost all the tested compounds were found to possess variable degrees of antimicrobial activities. Collectively, compounds 7c, 8c, 12b, 13a and 13b could be considered as possible agents with dual anticancer and antimicrobial activities.     

Design, synthesis, and docking studies of novel ofloxacin analogues as antimicrobial agents

A number of novel ofloxacin analogues were synthesized by modifying the carboxylic acid at C-6. To investigate the antimicrobial data on structural basis, in-silico docking studies of the tested compounds into the crystal structure of topoisomerase II using Autodock vina 4.0 program was performed in order to predict the affinity and orientation of the synthesized compounds at the activities. R ₂ values show good agreement with predicted binding affinities obtained by molecular docking studies. Also, it is verified by in-vitro antimicrobial screening, where all the compounds were most active against Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis. Among these compounds 3a, 3b, 3f showed good MIC (0.125?μg/ml).     

Design,synthesis, and molecular docking studies of novel quinoxaline derivatives as anticancer agents

As lung cancer was placed foremost part among other types of cancer in terms of mortality. Recent researches are widely focused on developing multi-targeted and site-specific targeted drug designs. In the present study, we designed and developed a series of quinoxaline pharmacophore derivatives as active EGFR inhibitors for the treatment of non-small cell lung cancer. The compounds were synthesized through a condensation reaction between hexane-3,4-dione and methyl 3,4-diaminobenzoate as a first step. Their structures were confirmed by ¹H-NMR, ¹³C-NMR, and HRMS spectroscopic methods. Cytotoxicity (MTT) were applied to determine anticancer activity of the compounds against breast (MCF7), fibroblast (NIH3 T3), and lung (A549) cell lines as EGFR inhibitors. Doxorubicin was used as a reference agent, compound 4i exhibited a significant effect among other derivatives with IC₅₀ = 3.902 ± 0.098 μM value against A549 cell line. The docking study showed that the best position on EGFR receptor could be observed with 4i . From the obtained evaluations of the designed series, compound 4i was a promising agent as EGFR inhibitor for further investigation and evaluation studies in the future.     

Synthesis andin vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.     

Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents

We report on the synthesis and biological evaluation of two series of 2,4,5-polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram-positive strains while they lack activity against Gram-negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a-f and those substituted with both the thioureido and thiosemicarbazide moieties 12a-f. Compounds 6f and 12f (R = 4-F-C(6)H(4)) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram-positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in-vitro anticancer activity according to the current one-dose protocol of the NCI. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five-dose assay.     

Synthesis, anticancer, and molecular docking studies of pyranone derivatives

A series of novel Pyran scaffolds of Thiazolidin-4-one [RA-3(a–d)] and Piperazine [BR (1–4)] were synthesized as potent bi-heterocyclic molecules. All the newly synthesized compounds were confirmed by spectral studies. These synthesized compounds were screened for in vivo anticancer activity. Compounds RA-3a, RA-3c, and BR-3 displayed the highest anticancer activity against Ehrlich Ascites Carcinoma cells and docking study of all the synthesized title compounds was carried out using Molegro Virtual Docker on GABARAPL1 (GABA_A receptor-associated protein-1 cancer receptor). These studies revealed the importance of Pyranone, Thiazolidnones, and Piperazine nucleus for their anticancer activity.     

Synthesis of some novel 2-substituted benzoxazoles as anticancer, antifungal, and antimicrobial agents

Benzoxazole derivatives show various types of biological properties such as antiviral, antineoplastic, anti-HIV-1, antitubercular, anthelmintic, antimicrobial, and antifungal activities. In the last few years 2-substituted benzoxazole derivatives have been studied extensively for their antitumor, antiviral, and antimicrobial activities. In an effort to identify new candidates that may be of value in designing new, potent, selective, and less toxic anticancer, antiviral, and/or antimicrobial agents, we synthesized 2-[(arylhydrazono) cyanomethyl]-5-chloro benzoxazoles (II), 2-[(arylidene)cyanomethyl]-5-halo benzoxazoles (III), and 2-[(cycloalkylidine)cyanomethyl]-5-chlorobenzoxazoles (IV), and tested them for anticancer, antifungal, and antibacterial activities. Some of these (compounds 11, 14) were found to possess anticancer activity and remarkable antifungal as well as antibacterial activities.     

Synthesis and characterization of flurbiprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents

A novel series of new flurbiprofen hydrazide derivatives 2-(2-fluorobiphenyl-4-yl)-N′-[(substituted phenyl/5-nitro-2-furyl)methylene]propanehydrazide (3a–k), 2-(2-fluorobiphenyl-4-yl)-N-(2-substituted-4-oxo-1,3-thiazolidine-3-yl)propanamide (4a–b, 4d–k), 2-[2-(2-fluorobiphenyl-4-yl) propanoyl]-N-substituted hydrazinecarbothioamide (5a–h) and 2-(2-fluorobiphenyl-4-yl)-N′-[(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene]propanehydrazide (6a–b, 6e and 6g) has been synthesized in this study. All synthesized compounds were screened for antimicrobial activity against various bacterial and fungal strains. Additionally, compounds were evaluated for the ability to inhibit Hepatitis C virus NS5B polymerase. The most active 4-thiazolidinone compound was 4k (SGK119) with 67.0 % and thiosemicarbazide compound was 5d (SGK123) with 69.50 % inhibition at 200 μM against hepatitis C virus NS5B RNA polymerase. Anticancer activity of the selected compounds (3i, 3j, 3h, 4d, 4i and 6b) was determined at a single dose towards the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI). 2-(2-Fluoro-4-biphenylyl)-N-[2-[4-(trifluoromethyl)phenyl]-4-oxo-1,3-thiazolidine-3-yl]propanamide 4d, containing thiazolidinone ring, demonstrated the most marked effect with 20.80 % growth percent on leukaemia cancer cell line SR at 10^?5 M. The results demonstrated that none of the compounds tested have anticandidal and antifungal activities, but two of them (4a and 4i) showed antibacterial inhibition against Micrococcus luteus, and Staphylococcus cohnii and Staphylococcus aureus, respectively.     

Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents

Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III _1–13 ) was confirmed by spectral characterization such as ¹H NMR, ¹³C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.     

新型鬼臼毒素衍生物的合成及抗肿瘤活性研究

目的通过对鬼臼毒素进行结构改造,寻找高效低毒的抗肿瘤先导化合物。方法运用拼合原理,将川芎嗪和天冬氨酸等结构片段引入鬼臼毒素结构中,通过1 H-NMR、13 C-NMR和HRMS确证结构;采用四甲基偶氮唑蓝(MTT)法评价化合物对人肺癌细胞A549、人肝癌细胞HepG2和人乳腺癌细胞MCF-7的活性及对人正常肝细胞L-02的毒性,并采用4′,6-二脒基-2-苯基吲哚(DAPI)染色法观察优势化合物对细胞核形态的影响。结果得到3个新型鬼臼毒素衍生物,其中化合物P-02(IC 50=0.1998±0.08μmol·L^-1)对A549的抑制作用与阳性药阿霉素相当(IC 50=0.1881±0.06μmol·L^-1),较依托泊苷(IC 50=8.55±0.43μmol·L^-1)提高了40倍;该化合物对L-02的毒性(IC 50=0.6701±0.176μmol·L^-1)明显小于阿霉素(IC 50=0.04684±0.02μmol·L^-1);DAPI染色结果表明,化合物P-02通过诱发A549细胞核碎裂产生细胞毒性。结论与临床化疗药物依托泊苷和阿霉素相比,将川芎嗪和氨基酸片段引入鬼臼毒素后可增强抗肿瘤活性,降低毒性,为新型鬼臼毒素类先导化合物的发现提供了参考。