Design, Synthesis and Anticancer Activities of Diaryl Urea Derivatives Bearing <i>N</i>-Acylhydrazone Moiety

A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their cytotoxic activities in vitro against human lung adenocarcinoma epithelial cell line (A549), human breast cancer cell line (MDA-MB-231) and human leukemia cell line (HL-60) by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Several compounds (1a, 1f and 1h) were further evaluated against human embryonic fibroblast, lung-derived cell line (WI38). The pharmacological results indicated that some compounds exhibited promising anticancer activities. In particular, compound 1f showed the most potent cytotoxicity against the tested three cell lines with IC50 values of 0.41?μM, 0.24?μM and 0.23?μM, respectively.     

Design, Synthesis and Anticancer Activity of 4-Morpholinothieno[3,2-<i>d</i>]pyrimidine Derivatives Bearing Arylmethylene Hydrazine Moiety

Three series of 4-morpholinothieno[3,2-d]pyrimidine derivatives containing arylmethylene hydrazine moiety (11a-f, 13a-k and 15a-h) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. The synthesized compounds were evaluated for their cytotoxicity against three cancer cell lines (H460, HT-29, MDA-MB-231). Most of them exhibited moderate to significant cytotoxicity and high-selectivity against one or more cell lines, especially compounds 11c, 13b, 15f and 15g possessing dramatically increased cytotoxicity as compared with the positive controls, which were further evaluated for six other cancer cell lines and one normal cell line. The most promising compound 11c, bearing 3,4-methylenedioxy phenyl group, showed remarkable cytotoxicity against H460, HT-29 and MDA-MB-231 cell lines with IC50 values of 0.003?μM, 0.42?μM and 0.74?μM, which was 1.6- to 290-fold more potent than GDC-0941.     

Ciprofloxacin–Isatin Hybrids and Their Antimycobacterial Activities

A series of diethylene glycol tethered ciprofloxacin–isatin hybrids 5a–j were designed, synthesized, and evaluated for their in vitro antimycobacterial activity against both drug‐sensitive and multidrug‐resistant (MDR) Mycobacterium tuberculosis strains in this paper. The preliminary results revealed that all hybrids with greater lipophilicity than the parent ciprofloxacin displayed considerable activity against the tested strains with minimum inhibitory concentration (MIC) in a range of 1.56–64 μg/mL. In particular, hybrid 5f (MIC: 1.56 and 2 μg/mL) with low cytotoxicity in VERO cell line was comparable with the parent ciprofloxacin (MIC: 0.78 and 2 μg/mL) against M. tuberculosis H₃₇Rv and MDR tuberculosis strains and ≥16‐fold more potent than isoniazid and rifampicin (MIC: >128 and 32 μg/mL, respectively) against MDR tuberculosis, suggesting that it may serve as a new and promising candidate for further study.     

Synthesis and bio-evaluation of phenothiazine derivatives as new antituberculosis agents

Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for anti-tuberculosis activities against Mycobacterium tuberculosis H₃₇R_V. In comparison with mother compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis agents.     

Synthesis and antimicrobial activity of sulphamethoxazole-based ureas and imidazolidine-2,4,5-triones

Progression of drug resistance among bacterial and fungal pathogens justifies the development of novel antimicrobial agents. Thus, a series of novel sulphamethoxazole-based ureas and imidazolidine-2,4,5-triones have been designed and synthesised. The urea derivatives were obtained by the reaction of sulphamethoxazole and isocyanates, and their cyclisation to imidazolidine-2,4,5-triones was performed via oxalyl chloride. All synthesised derivatives were evaluated in vitro to determine their activity against gram-positive and gram-negative bacteria, fungi, Mycobacterium tuberculosis, and atypical mycobacteria and their cytotoxicity. The growth of mycobacteria was inhibited within the range of 4–1000 µM and M. tuberculosis was the least-susceptible strain. 4-(3-Heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulphonamide was identified as the most promising compound because it exhibited the highest activity against atypical mycobacteria at minimum inhibitory concentrations, from 4 µM, and with acceptable toxicity (selectivity indices for M. avium and M. kansasii higher than 16 and 62.5, respectively). Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, were inhibited at concentrations starting from 125 µM, whereas the investigated derivatives exhibited almost no antifungal potency and activity against gram-negative species.     

Arylthio analogs of 5,8-quinolinedione: Synthesis,characterization, antibacterial,and antifungal evaluations

Abstract

A set of bis(arylthio) substituted 5,8-quinolinedione derivatives were synthesized and investigated for their in vitro antimicrobial effect. The antibacterial and antifungal activities of 6,7-bis(arylthio)-5,8-quinolinedione (4a–f) and 6,7-bis(arylthio)-2-methyl-5,8-quinolinedione (5a–f) were evaluated against four gram-negative bacteria, three gram-positive bacteria, and three fungi strains. The bis(methoxyarylthio) 5,8-quinolinedione analogs presented better activity against especially gram-positive bacteria compared to bis(halogenarylthio) 5,8-quinolinedione analogs. Bis(3-methoxyarylthio) 5,8-quinolinedione (4e) had the same activity of the reference drug against Staphylococcus aureus. Bis(2-methoxyarylthio) 5,8-quinolinedione (4f) showed two-and-a half-fold better activity with 89.69?μM against Enterococcus faecalis, and two-fold better activity with 11.20?μM against Staphylococcus epidermidis. Bis(2-methoxyarylthio)-2-methyl-5,8-quinolinedione 5f exhibited five-fold higher antibacterial activity with 43.44?μM against E. faecalis and also eight-fold activity of the reference drug with 2.71?μM against S. epidermidis.     

Synthesis,spectral characterization,and biological studies of 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-thione derivatives

The reaction of 3,4-dichlorophenyl-1,3,4-oxadiazole-2( 3H )-thione with piperidine derivatives via Mannich reaction was used to generate eleven novel compounds in moderate to good yields. Synthesized molecules were characterized according to their structure with ¹H NMR, ¹³C NMR and FT-IR spectral foundations, which were compatible with literature informations. Antimicrobial activity and cytotoxicity studies were done by disc diffusion and NCI-60 sulphordamine B assay methods. The antimicrobial test results revealed that synthesized compounds have better activity against gram-positive species than gram-negative ones. A total analysis of the antibacterial, antifungal, and antiyeast activity revealed that newly synthesized compounds were really active against Bacillus cereus , Bacillus ehimensis, and Bacillus thuringiensis species . For cytotoxicity, among three different cancer cell lines (HCT116, MCF7, HUH7) compounds 5c, 5d, 5e, 5f, 5g, 5i, 5j and 5k were seemed especially effective on HUH7 cancer cell line via moderate to good activity. More significantly, against liver carcinoma cell line (HUH7) most of the compounds of the series ( 5c-5g and 5i-5j ) have better IC₅₀ values (IC₅₀= 18.78 µM) than 5-Florouracil (5-FU) and also compound 5d possessed 10.1 µM value, which represents good druggable cytotoxic activity. Further, the molecules were also screened for in silico chemoinformatic and toxicity data to gather the predicted bioavailibity and safety measurements.     

Synthesis and in vitro Antimycobacterial Activity of Moxifloxacin Methylene and Ethylene Isatin Derivatives

A series of novel moxifloxacin methylene and ethylene isatin derivatives with remarkable improvement in lipophilicity, compared to the parent moxifloxacin, was designed, synthesized and characterized by 1H NMR, MS and HRMS. These derivatives were initially evaluated for their in vitro antimycobacterial activity against M. smegmatis CMCC 93202. Compounds 3a―3f, 5a, 5f and 5j were chosen for the further evaluation of their in vitro activity against Mycobacterium tuberculosis(MTB) H37Rv ATCC 27294 and MDR-MTB 09710. All the target compounds[ minimum inhibitory concentration(MIC): 0.39―>16 μg/mL] were far more active than rifampin(MIC: 2.0―>256 μg/mL), but less active than moxifloxacin(MIC: 0.1―1.0 μg/mL) against the three tested strains. The most active compounds 3a and 3c were found to be 2―64 fold more potent than isoniazid and rifampin against M. smegmatis CMCC 93202, 2 fold more potent than rifampin against MTB H37Rv ATCC 27294, and 16―>64 fold more potent than ethambutol, isoniazid and rifampin against MDR-MTB 09710.     

Synthesis and cytotoxic evaluation of novel N-methyl-4-phenoxypicolinamide derivatives

A series of N-methyl-4-phenoxypicolinamide derivatives were synthesized and evaluated in vitro for their cytotoxic activity against A549, H460 and HT29 cell lines. Pharmacological data indicated that some of the target compounds possessed marked antiproliferative activity, superior to that of the reference drug sorafenib. As the most promising compound, 8e exhibited potent cytotoxicity with the IC(50) value of 3.6, 1.7 and 3.0 μM against A549, H460 and HT-29 cell lines, respectively.     

Glycerol Mediated Synthesis,Biological Evaluation,and Molecular Docking Study of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines as Potent Antitubercular Agents

A series of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines were synthesized through one‐pot four‐component Hantzsch condensation of 1,3‐diphenyl‐1H‐pyrazole‐4‐carbaldehydes, ammonium acetate, dimedone, and alkyl acetoacetate in glycerol as a green reaction medium. The structures of the compounds are verified by spectroscopic methods and screened for their antimicrobial activity against Mycobacterium tuberculosis H37RV strain. Almost all the synthesized derivatives reveal excellent antitubercular activity based on minimum inhibitory concentration. Especially the compounds 5h and 5k exhibit outstanding antitubercular activity with minimum inhibitory concentration 1.6 μg/mL. In addition, molecular docking study of synthesized scaffolds against enoyl‐acyl carrier protein reductase from M. tuberculosis was performed to propose the binding modes.     

Synthesis,characterization and biological evaluation of some novel sulfonylthiosemicarbazides

Abstract

A series of thiosemicarbazides were synthesized and structurally characterized by spectroscopic techniques (NMR, FT-IR) besides elemental analysis. These compounds were evaluated for their cytotoxicity against human breast cancer cell line MCF7 and prostate cancer cell line PC3 and nonmalignant fibroblast L929 cell line by MTT assay. Among the compounds, N-[2-(4-chlorophenyl)ethyl]-2-[(4-methylphenyl)sulfonyl]hydrazinecarbothioamide (3d) and 2-[(4-methylphenyl)sulfonyl]-N-[4-(trifluoromethoxy)phenyl]hydrazinecarbothioamide (3f) were found to display significant cytotoxicity with IC₅₀ of 13.87?μM (against PC3 cell line) and 1.47?μM (against MCF7 cell line), respectively. These compounds were non-cytotoxic to normal cell line with IC₅₀>100?μM. Western blotting studies demonstrated that compound 3f induced apoptosis and caused cell death in the MCF7 and PC3 cell lines via an increase in Bax protein expression and a slight decrease in Bcl-2 protein expression. The gene expression ratio Bax/Bcl-2 showed the induction of mitochondrial apoptosis in cancer cell lines. All of synthesized compounds have also been tested for antioxidant activity and all compounds achieved strong inhibition of the DPPH radical. These findings showed that compound 3f, displays potential to be further explored in the development of new anticancer agents.     

Design,Synthesis, and In Vitro Anti‐mycobacterial Evaluation 1H‐1,2,3‐triazole‐tethered Ciprofloxacin and Isatin Conjugates

Eight novel 1H‐1,2,3‐triazole‐tethered ciprofloxacin (CPFX) isatin conjugates 5a – h with greater lipophilicity compared with CPFX were designed, synthesized, and evaluated for their in vitro anti‐mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis (MTB) H₃₇Rv. The preliminary results showed that all hybrids (MIC: 12.5–100 μg/mL) exhibited considerable activity against M. smegmatis , but less active than the parent CPFX (MIC: 6.25 μg/mL) and the reference INH (MIC: 0.78 μg/mL). Against MTB H₃₇Rv, all hybrids displayed excellent inhibitory activity with MICs ranging from 1.56 to 25 μg/mL, particularly, 5h (MIC: 1.56 μg/mL) was twofold more active CPFX (MIC: 3.12 μg/mL), warrant further investigations.     

Design,Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC₅₀ = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79%) activity. Compound 4g was found to be the most active compound against EGFR (IC₅₀ = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.     

Synthesis,Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (¹H, ¹³C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 μM. In addition, six other synthesized compounds, 5a and 5c–5g, exhibited moderate activity, with MIC ranges between 60 μM to 140 μM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 μM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand–receptor interactions, and to hypothesize potential refinements for the compound.     

Synthesis,antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB) with MIC 12.5?μg/mL. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.     

Synthesis and cytotoxicity of indolopyrrolemaleimides

A series of indolopyrrolemaleimides have been synthesized and evaluated for their cytotoxicity in vitro against human leukemia cell line and four human solid cancer cell lines. Some of the compounds showed high or mediate activity against the lines. 6dc is the most promising compound among them. The inhibition toward topoisomerase I was also studied.     

硝基呋喃亚甲基哌啶类化合物的合成与抗结核活性

结核是由结核分枝杆菌引起的一种慢性呼吸道传染病,对人类的健康构成严重威胁。 本文利用药效团拼接原理,将片段硝基呋喃和苯基噻唑组合,得到了19个2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)噻唑(5)和2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-4-苯噻唑(6)系列化合物,测试了所有化合物在1和0.1 μmol/L浓度下对结核分枝杆菌H37Ra的抑制率。 构效关系分析表明,苯环上有取代基有利于活性,且苯环上对位取代普遍优于间位和邻位取代,对位吸电子基团取代活性优于对位供电子基团取代活性。在苯环对位吸电子基团取代中,—CF₃取代的化合物2-(1-((5-硝基呋喃-2-基)甲基)哌啶-4-基)-4-(4-三氟甲基)苯基)噻唑(6f)活性最高,在1和0.1 μmol/L浓度下,抑制率分别为99.6%和93.4%。 鉴于新化合物具有抗结核高活性,化合物6f可作为抗结核候选化合物进一步研究。     

Dicationic liquid mediated synthesis of tetrazoloquinolinyl methoxy phenyl 4-thiazolidinones and their antibacterial and antitubercular evaluation

In a search of new potentially active antitubercular agents here we have synthesized 3-substituted phenyl-2-(4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)phenyl)thiazolidin-4-ones (8a–l) and evaluated their antibacterial, particularly antitubercular activity. These have been conveniently synthesized by performing one–pot cyclocondensation of 4-(tetrazolo[1,5-a]quinolin-4-ylmethoxy)benzaldehyde, anilines and mercaptoacetic acid in dicationic ionic liquid, (3-methyl-1-[3-(methyl-1H-imidazolium-1-yl)propyl]-1H-imidazolium dibromide [C₃(MIM)₂–2Br]) and obtained excellent yields of (8a–l). 4-Thiazolidinones (8a–l) were thoroughly characterized by their spectral analyses. These compounds have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra and Mycobacterium bovis (BCG). The compounds 8a, 8c, and 8e exhibited notable in vitro antitubercular activity compare to the reference, Rifampicin. Molecular docking study has also been performed to know the binding mode of these analogs in to the active site of DprE1 enzyme. The synthesized compounds were also evaluated for their in vitro antibacterial activity and amongst them compound 8k has shown moderate activity against both gram-negative and gram-positive bacterial strains.     

Synthesis of novel thiazol-5-ylpyrimidine derivatives and their antimicrobial evaluation

Novel thiazol-5-ylpyrimidine derivatives were designed and synthesized. The chemical structures of all new synthesized compounds were assigned by studying their elemental analyses and spectral data (FT-IR, ¹HNMR, ¹³C NMR, and MS). The target compounds, 8 and 9a-9d were evaluated for their antimicrobial activity in vitro against gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, gram-negative bacteria, Salmonella abony and Escherichia coli and fungi, Aspergillus flavus and Fusarium oxysporum. In particular, compounds 9a-9c exhibited moderate to good activity against gram-positive bacteria, S. aureus, gram-negative bacteria, S. abony and fungus, Fusarium oxysporum in comparison with reference drugs.     

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

Abstract

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13?g (IC₅₀ = 0.514?μM) and 13o (IC₅₀ = 0.275?μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511?μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.