Design,synthesis,in vitro evaluation of tetrahydropyrimidine-isatin hybrids as potential antibacterial,antifungal and anti-tubercular agents

A series of 5-substitued-3-(5-(4-(furan-2-yl)-6-methyl-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,3,4-thiadiazol-2- ylimino)indolin-2-one derivatives were synthesized,characterized and were screened for anti-bacterial,anti-fungal and antitubercular activity.     

Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design,synthesis and biological evaluation

A series of novel 2,4-diaminopyrimidine-modified compounds was designed and synthesized. Compound 14 showed micromolar dual inhibitory effect on both FP-2 and PfDHFR, and potential inhibition to the proliferation of P. falciparum 3D7 strain and chloroquine-resistant P. falciparum Dd2 strain.     

Design, synthesis, and biological evaluation of beta-ketosulfonamide adenylation inhibitors as potential antitubercular agents

[reaction: see text] The antitubercular nucleoside antibiotics 1 and 2 were recently described that inhibit the adenylate-forming enzyme MbtA and disrupt biosynthesis of the virulence-conferring siderophore known as mycobactin in Mycobacterium tuberculosis. Herein, we report efforts to refine this inhibitor scaffold by replacing the labile acylsulfamate linkage (highlighted) with the more chemically robust beta-ketosulfonamide linkage of 3 and 4.     

Stereocontrolled synthesis of a potent antimalarial alkaloid, (+)-febrifugine

A novel and stereocontrolled synthetic path to a potential antimalarial piperidine alkaloid, (+)-febrifugine, was established by employing the reductive deamination and simultaneous recyclization of a proline derivative with samarium diiodide, as a key step.     

2-巯基苯并咪唑衍生物的设计、合成及抗肿瘤活性研究

为了从苯并咪唑类衍生物中寻找新的活性化合物,以溴乙酸作为起始原料,设计合成了17个2-巯基苯并咪唑衍生物4a～4q。采用噻唑蓝(MTT)法测试了目标化合物对人宫颈癌细胞(He La)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2)、人非小细胞肺癌细胞(A549)的增殖抑制活性。结果显示,大部分化合物具有较好的抗肿瘤活性,其中,((1H-苯并[d]咪唑-2-基)硫基)-1-(4-二苯甲基哌嗪-1-基)乙烷-1-酮(4l)对HepG2细胞的抑制活性最好,IC_(50)值为12. 62±0. 78μmol/L,接近于对照药品吉非替尼(9. 72±0. 38μmol/L)。此外,利用分子对接方法对目标化合物的构效关系进行了讨论。     

Design,synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents

Inhibition of mycobacterial membrane protein large 3(MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compound...     

N-Mannich bases of benzimidazole as a potent antitubercular and antiprotozoal agents: Their synthesis and computational studies

Abstract

This article dealing with the microwave assisted synthesis of N-Mannich bases of pyridine clubbed with two different benzimidazole cores with their micromolar biological potency. All the synthesized compounds were evaluated for their in-vitro antibacterial, antimycobacterial and antiprotozoal potency. One of the final compound was found to be most active against M. tuberculosis (MIC = 3.125?µM) in the primary screening. N-Mannich bases of benzimidazole with pyridine-3-amine and 5-methyl-pyridine-2-amine showed potency against L. mexicana and T. cruzi respectively with IC₅₀ value 0.25 and 1.02?µg/mL. Compound 4a showed good binding energy in the active pocket of receptor (PDB: 4cod) with ?11.013 docking score. The stability of docked complex was validated by performing Molecular dynamics (MD) up to 20?ns simulation time. In silico ADME parameters and toxicity predicted that the active compounds belong to the Class IV GHS with LD₅₀ value 1360?mg/kg and hence found to be mildly toxic.     

Design,synthesis and in vitro biological evaluation of novel 4-methoxy-5-hydroxycanthin-6-one derivatives as potential anti-tumor agents

Abstract

Canthin-6-one analogue, 4-methoxy-5-hydroxycanthin-6-one (CAN1) was isolated from Picrasma quassioides (D.Don) Benn., and a series of derivatives containing the CAN1 framework were designed, synthesized, and evaluated for anti-proliferative activity against two human cancer cell lines, HepG2 and HCT116. Among these compounds, the most representative compound d exhibited better anti-proliferative activities in vitro compared with the positive control Fluorouracil (5-FU), with IC₅₀ values of 5.05?μM (HepG2) and 6.65?μM (HCT116), respectively. Compound d triggered more significant HepG2 cell apoptosis than 5-FU did in a dose-dependent manner. Furthermore, western blot assay indicated that d could enhance the expression of p65 while promoting pro-apoptotic proteins and suppressing the anti-apoptotic proteins in a dose-dependent manner. All these results demonstrated that d might be a potential agent for cancer therapy deserving further exploring.     

Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands

Gold(III) thiosemicarbazone complexes derived from [Au(damp-C¹,N)Cl₂] (2), where damp = dimeth-ylaminoethylphenyl, have been synthesized. The compounds were characterised using various spectroscopic and analytical techniques, including NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis. The gold complexes were screened for in vitro antimalarial and antitubercular activity. Although incorporation of the gold(III) centre into thiosemicarbazone scaffolds enhanced their efficacy against the malaria parasite Plasmodium falciparum, this trend was not observed for the antitubercular activity of selected thiosemicarbazones against the Mycobacterium tuberculosis virulent strain H₃₇Rv.     

Synthesis and biological evaluation of some novel thiadiazole-benzofuran hybrids as potential antitumor agents

Two series of novel 1,3,4-thiadiazole-benzofuran and 1,3,4-thiadiazole-furochromene derivatives were synthesized through heterocyclization of alkyl 2-(1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethylidene)hydrazine-1-carbodithioate 3a–f and 2-(1-(5-methoxy-8-methyl-2,6-dioxo-2,6-dihydropyrano[3,2-g]chromen-3-yl)ethylidene)hydrazinecarbothioamide 9a,b with various hydrazonoyl halides, respectively. The structure of the newly synthesized products was elucidated through elemental analysis, spectral data and alternative routes whenever possible. Ten new compounds were evaluated for their anticancer activity against the human breast carcinoma (MCF-7) cell lines in comparison with reference doxorubicin using MTT assay. The results showed that some new compounds have promising anticancer activity.     

Design,synthesis, and biological evaluation of indolylidinepyrazolones as potential anti-bacterial agents

A series of indolylidinepyrazolones were synthesized using a simple, green, and effective route and evaluated as anti-bacterial agents. The compounds were further studied via structure-guided docking study. One of the compounds exhibiting H-bonding interactions with conserved residue Arg144 turned out to be the most potent compound of the series. The minimum inhibitory concentration values ranged from 50 to 25 μg/mL against Staphylococcus aureus in their anti microbial evaluation.     

Asymmetric synthesis and biological evaluation of 3-nitro-2H-chromenes as potential antibacterial agents

A one-pot organocatalytic domino Henry/Michael/dehydration sequence of various salicylaldehyde derivatives with nitromethane as a dual-nucleophile is disclosed. This straightforward strategy assembles the optically active (R)-2-alkyl 3-nitro-2H-chromenes with good to excellent enantioselectivities (up to 93% ee) and a broad substrate scope. Preliminary in vitro antibacterial evaluation revealed most of the chiral 3-nitro-2H-chromene derivatives exhibit antibacterial activities against four Gram-positive bacteria. Compound 3p with two bromine substituents on the core scaffold was shown to be the best antibacterial agent in the series against S. aureus, B. subtilis and Bacillus cereus with minimal bactericidal concentration (MBC) values of 4?μg/mL, and against Staphylococcus epidermidis with a MBC value of 8?μg/mL.     

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.     

Design,synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Background

Glycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.

Results

The result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC₅₀ > 50 μM). It was worth noting that 8a had a superior cytotoxicity effect on Hela cells (IC₅₀ = 8.54 μM) than on other cancer cell lines (IC₅₀ > 15 μM). And it also indicated that 8a showed lower cytotoxicity (IC₅₀ > 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC₅₀ < 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD₅₀ of 8a exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that 8a could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.

Conclusions

Compared with GA, target compounds demonstrated better anti-tumor activity, among which 8a was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with trans olefinic bond group show higher antitumor activity than those without olefinic bond, such as 1a > 1b, 6a > 2b, 8a > 3b, 9a > 4b. In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as 4a, 6a, 7a, 8a. However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.

     

Design and synthesis of oxaprozin-1,3,4-oxadiazole hybrids as potential anticancer and antibacterial agents

In the present study, we report design, synthesis and screening of new novel 5-substituted-2-mercapto-1,3,4-oxadiazole analogues appended to oxaprozin for their in vitro anticancer and antibacterial activity. The synthesised compounds were characterized using various spectroscopic techniques. Furthermore, the structure of 5b (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-(ethylthio)-1,3,4-oxadiazole) was unequivocally confirmed by X-ray analysis. Among the series 5c (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-(propylthio)-1,3,4-oxadiazole) showed most promising anticancer activity against A549 cancer cell line and all the reported analogues manifested satisfactory safety profiles against human normal cell line HEK293T. The products exhibited good antibacterial activity and among the tested 5j (2-(2-[4,5-diphenyloxazol-2-yl]ethyl)-5-([4-fluorobenzyl]thio)-1,3,4-oxadiazole) exhibited most potent.     

Microwave-assisted,rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity

A rapid and efficient synthesis of 2-vinylquinolines via trifluoromethanesulfonamide-mediated olefination of 2-methylquinoline and aldehyde under microwave irradiation is reported. Biological evaluation of these scaffolds demonstrates that 2-vinylquinolines 3x-3z possess excellent antimalarial activities against chloroquine-resistant Dd2 strain of Plasmodium falciparum (IC₅₀ < 100 nM).     

Synthesis and antitubercular activity evaluation of 4-furano-coumarins and 3-furano-chromones

The synthesis of novel 4-furano-coumarins and 3-furano-chromones has been achieved using silver-mediated oxidative C–H/C–H functionalization of 4-ethynylcoumarin/3-ethynylchromone with ethyl acetoacetate in 80%–90% and 82%–90% yields, respectively. The structure of the synthesized compounds was established on the basis of their spectral data analysis and the structure of one of the 4-furano-coumarins has been further confirmed on the basis of its X-ray crystallographic study. All eight synthesized 4-furano-coumarins and 3-furano-chromones exhibited moderate antitubercular activity against sensitive reference strain H37Rv of Mycobacterium tuberculosis.     

Design,synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents

In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring（5a-5h）,the isoquinolinium ring（6a-6c） and the quinolinium ring（7a-7e） linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line（H460） by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC₅₀ values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC₅₀ = 0.006μmol/L) was 216.7 times more active than MKT-077(IC₅₀ = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.     

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones, 2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro. The new compounds revealed excellent in vitro antifungal activity with broad spectrum. The structure-activity relationships (SARs) of the derivatives were analyzed. Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole, especially against Trichophyton rubrum and Microsporum gypseum. This study provides a series of novel lead compounds for the development of non-azole antifungal agents.