Design,synthesis and anticancer activity of novel pyrimidine and pyrimidine-thiadiazole hybrid glycosides

Abstract

New 1,3,4-thiadiazole thioglycosides linked to substituted pyrimidines were synthesized via glycosylation of 1,3,4-thiadiazole thiol compounds. Also, novel 1,2,3-triazole derivatives linked to carbohydrate units were prepared using the standard click chemistry conditions employing the Cu(I)-catalyzed azide-alkyne cycloaddition of substituted-aryl-azides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using various spectroscopic techniques, such as IR, ¹H NMR, ¹³C NMR and elemental analyses. The cytotoxic activities of the prepared compounds were investigated in vitro against human liver cancer (HepG-2) and human breast adenocarcinoma (MCF7) cell lines. In addition, the biological evaluation of the new compounds involved the investigation of their effects on a human normal retinal pigmented epithelial cell line (RPE1) using the MTT assay.     

Search for human DNA topoisomerase II poisons in the group of 2,5-disubstituted-1,3,4-thiadiazoles

Abstract

A series of six 2,5-disubstituted 1,3,4-thiadiazole derivatives was synthesized and examined for cytotoxic activity in MCF-7 and MDA-MB-231 breast cancer cells. MTT assay confirmed that 2-(3-fluorophenylamino)-5-(3-hydroxyphenyl)-1,3,4-thiadiazole (2), 2-(4-bromophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (3), 2-(4-fluorophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (4), had ability to inhibit MCF-7 and MDA-MB-231 cells proliferation. The IC₅₀ values for the mentioned compounds ranged between 120 and 160?μM (with respect to MCF-7 cells) and from 70 to 170?μM (with respect to MDA-MB-231 cells). It turned out, moreover, that compound 2 is a human topoisomerase II (topoII) catalytic inhibitor whereas the two other compounds (i.e. 3 and 4) are capable of stabilizing DNA-topoII cleavage complex and thus are topoII poisons.     

Synthesis and antimicrobial activity of new 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this study, new 3-[(1(2H)-phthalazinone-2-yl(methyl/ethyl]-4-aryl-1,2,4-triazole-5-thione and 2-[[1(2H)-phthalazinone-2-yl]methyl/ethyl]-5-arylamino-1,3,4-thiadiazole derivatives were synthesized. Antimicrobial properties of the title compounds were investigated against two Gram (+) bacteria (S. aureus, B. subtilis), two Gram ( ? ) bacteria (P. aeruginosa, E. coli) and two yeast-like fungi (C. albicans and C. parapsilosis) using the broth microdilution method. Generally the compounds were found to be active against B. subtilis and the fungi. Derivatives carrying a 1,3,4-thiadiazole ring generally showed higher antimicrobial activity against B. subtilis and the fungi when compared to other synthesized compounds.     

New 5-(nitroheteroaryl)-1,3,4-thiadiazols containing acyclic amines at C-2: synthesis and SAR study for their antileishmanial activity

A novel series of 5-(5-nitrofuran-2-yl)-and 5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazole-2-amines bearing acyclic amine at C-2 position of thiadiazole ring were synthesized and evaluated in vitro against promastigote and amastigote forms of Leishmania major. The structure-activity of series was investigated by studying 40 compounds. The most active derivatives were hydroxypropylamino- and methoxypropylamino- analogs of 5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazole (compounds 29 and 32, respectively) with highest selectivity index (SI >12).     

Synthesis of new 2,5-disubstituted-1,3,4-thiadiazole derivatives and their in vivo anticonvulsant activity

A series of 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized by the reaction of 3-(2-cyanopropan-2-yl)-N-(5-(piperazine-1-yl)-1,3,4-thiadiazol-2-yl)benzamide with various sulfonyl chlorides and evaluated for their anticonvulsant activity in MES test. Rotorod method was employed to determine the neurotoxicity. The purity of the compounds is confirmed on the basis of their elemental analysis. The structures of all the new compounds are established on the basis of ¹H NMR and mass spectral data. Out of fifteen compounds, three were found to be potent anticolvunstants. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg).     

2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole analogues: Antifungal activity in vitro against <Emphasis Type="Italic">Candida</Emphasis> species

The antifungal activity in vitro of the newly synthesized and previously reported compounds of 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole series was evaluated. Their structures were confirmed by elemental analyses and IR, ¹H and ¹³C NMR and mass spectra. The azole-resistant clinical isolates of Candida albicans and no-albicans Candida spp. were used in the antifungal tests. Some compounds exhibit higher activities than the comparatively studied antifungal drugs. Amino-1,3,4-thiadiazole derivatives exhibited higher (than other analogues) antifungal effects against Candida no-albicans spp. than against C. albicans. Derivatives with strong antifungal activity have a narrow range of lipophilicity values determined by the Villar approach.     

Relationship between the Structures and Cytotoxic Activities of 1,3,4-Thiadiazolo[3,2-a]pyrimidines

1,3,4-Thiadiazole derivatives having a partial structure of 2-ethylsulfonyl-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (TPSO₂-2) were synthesized, and their chemical reactivities and biological activities were investigated. TPSO₂-2 readily reacted with SH compounds and showed a high inhibitory effect against “SH enzyme,” but 2-acetylamino-5-ethylsulfonyl-1,3,4-thiadiazole (AEST), a TPSO₂-2 analog without a pyrimidine structure, did not react with those compounds and showed a smaller inhibitory effect against the enzyme. Furthermore, TPSO₂-2 showed a strong anti-yeast activity, while AEST did not. It is presumed that not only the electron-withdrawing sulfonyl group at the 2-position but also the pseudopurine skeleton appear to be responsible for revealing the biological and chemical activities of TPSO₂-2.     

Diterpenoids from Wedelia prostrata and Their Derivatives and Cytotoxic Activities

One new ent‐kaurane diterpenoid, 11β,16α‐dihydroxy‐ent‐kauran‐19‐oic acid ( 1 ), together with eight known analogues 2 – 9 were isolated from the aerial parts of Wedelia prostrata. One of the acidic diterpenoids, kaurenoic acid ( 3 ), was converted to seven derivatives, 10 – 16 . All compounds were evaluated for their cytotoxic activity in vitro against human leukemia (K562), liver (HepG‐2), and stomach (SGC‐7901) cancer cell lines. Only four kaurenoic acid derivatives, 13 – 16 , with 15‐keto and substitutions at C(19) position, exhibited notable cytotoxic activities on these tumor cell lines with IC₅₀ value ranging from 0.05 to 3.71 μm . Compounds 10 – 12 , with oxime on C(15) showed moderate inhibitory effects and compounds 1 – 9 showed no cytotoxicities on them. Structure–activity relationships were also discussed based on the experimental data obtained. The known derivative, 15‐oxokaurenoic acid 4‐piperdin‐1‐ylbutyl ester ( 17 ), induced typical apoptotic cell death in colon SW480 cells upon evaluation of the apoptosis‐inducing activity by flow‐cytometric analysis.     

Synthesis and in vitro antimicrobial activity of novel N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class

In this study, a series of novel 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazole (6a–g) and 1,3,4-oxadiazole (7a–g, 8) were synthesized from N-(6-chlorobenzo[d]thiazol-2-yl) hydrazine carboxamide derivatives of benzothiazole class. Antimicrobial properties of the title compound derivatives were investigated against one Gram (+) bacteria (Staphylococcus aureus), three Gram (?) bacteria (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and five fungi (Candida albicans, Aspergillus niger, Aspergillus flavus, Monascus purpureus and Penicillium citrinum) using serial plate dilution method. The investigation of antibacterial and antifungal screening data revealed that all the tested compounds showed moderate to good inhibition at 12.5–100?µg/mL in DMSO. It has been observed that triazolo-thiadiazole derivatives are found to be more active than 1,3,4-oxadiazole derivatives against all pathogenic bacterial and fungal strains.     

Synthesis and bioactivities of novel thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety

A series of new thioether/sulfone compounds containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/1,3,4-thiadiazole moiety were synthesized, the structures of all products were confirmed by IR, ¹H NMR, ¹³C NMR, and element analysis. Preliminary antifungal activity test showed that compound 8a exhibited moderate antifungal activity against Fusarium oxysporum at 50 μg/mL. Preliminary antiviral activity results showed that compounds 7a, 7c, 7d, 8a, and 9a displayed high antiviral activity against tobacco mosaic virus. The present work demonstrates that thioether/sulfone heterocyclic derivatives could be considered as new lead compounds for antiviral studies.     

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6-Methylpyridine Moiety

A series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles ( 15a – t and 16a – f ) were synthesized and their antibacterial activities were evaluated. More than half of the compounds showed moderate or strong antibacterial activity. Among them, compounds 15t (MIC=1–2 μg/mL) and 16d (MIC=0.5 μg/mL) showed the strongest antibacterial activities. Notably, compound 16d did not exhibit cytotoxicity in HepG2 cells and did not show hemolysis like the positive control compound Gatifloxacin. The results suggest that compound 16d should be further investigated as a candidate antibacterial agent.     

2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis,evaluation of in vitro leishmanicidal activity,and mechanism of action

The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4′-bipiperidin]-1′-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.     

Synthesis and Anticancer Activity of New 1,3,4-Thiadiazolyl-1,2,4-Triazolyl and 1,3,4-Oxadiazolyl Hybrids,Their Thioglycosides,and Acyclic Analogs

Russian Journal of Bioorganic Chemistry - New Furan, 1,3,4-thiadiazole and 1,2,4-triazole hybrid compounds and their 1,3,4-oxadiazole hybrid derivatives were synthesized. The thioglycoside...     

Synthesis and in vitro antimicrobial activity of new 4-phenyl-5-methyl-4H-1,2,4-triazole-3-thione derivatives

This study presents the synthesis, spectral analysis and antimicrobial evaluation of a new series of substituted 1,2,4-triazole (5a–i) and 1,3,4-thiadiazole derivatives (9a, c, g, h). New compounds were obtained by cyclization reaction of acyl thiosemicarbazide derivatives in the presence of alkaline and acidic media. All synthesized compounds were screened for their in vitro antimicrobial activities. Nine of the compounds had potential activity against Gram-positive bacteria (MIC?=?3.91–500 µg/mL). Some compounds showed good activity especially against: Micrococcus luteus ATCC 10240 (MIC?=?3.91?31.25 µg/mL), Bacillus subtilis ATCC 6633 (MIC?=?15.63? 62.5 µg/mL), and Staphylococcus aureus ATCC 25923 (MIC?=?15.63?125 µg/mL).     

Synthesis and Insecticidal Activities of Novel 1,3,4-Thiadiazole 5-Fluorouracil Acetamides Derivatives: An RNA Interference Insecticide

A series of novel 1,3,4-thiadiazole 5-fluorouracil acetamides derivatives were designed and synthesized. Their structures were confirmed by infrared, ¹H NMR spectroscopy, and elemental analysis. The insecticidal activities against Tetranychus cinnabarinus and Aphis craccivora of these new compounds were evaluated. The bioassay tests showed that most of these title compounds possessed a good combination of stomach toxicity as well as contact toxicity against Tetranychus cinnabarinus and Aphis craccivora. In particular, the insecticidal activity of the title compound IVe against Aphis craccivora was better than the commercialized thiacloprid and was also comparable to another commercialized product, imidacloprid. The introduction of fluorines to meta and para-position of the benzene ring was essential for high bioactivity.     

Synthesis and antimicrobial activity of new 1,2,4-triazole and 1,3,4-thiadiazole derivatives

In this study, new 3-[(1(2H)-phthalazinone-2-yl(methyl/ethyl]-4-aryl-1,2,4-triazole-5-thione and 2-[[1(2H)-phthalazinone-2-yl]methyl/ethyl]-5-arylamino-1,3,4-thiadiazole derivatives were synthesized. Antimicrobial properties of the title compounds were investigated against two Gram (+) bacteria (S. aureus, B. subtilis), two Gram ( - ) bacteria (P. aeruginosa, E. coli) and two yeast-like fungi (C. albicans and C. parapsilosis) using the broth microdilution method. Generally the compounds were found to be active against B. subtilis and the fungi. Derivatives carrying a 1,3,4-thiadiazole ring generally showed higher antimicrobial activity against B. subtilis and the fungi when compared to other synthesized compounds.     

Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity

A series of new imidazole carboxylic esters (carbamates) and N-acylimidazole derivatives of betulin and betulinic acid (14–29) have been synthesized. The new compounds were screened for in vitro cytotoxicity activity against human cancer cell lines HepG2, Jurkat and HeLa. A number of compounds have shown IC₅₀ values lower than 2 μM against the cancer cell lines tested and the vast majority has shown a better cytotoxicity profile than betulinic acid, including the betulin derivatives. N-Acylimidazole derivatives 26 and 27 (IC₅₀ 0.8 and 1.7 μM in HepG2 cells) and the C-3 carbamate derivative 16 (IC₅₀ 2.0 μM in HepG2 cells) were the most promising compounds. Based on the observed cytotoxicity, structure–activity relationships have been established.     

Design,synthesis and evaluation of novel (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit as anticancer agents

A series of (S)-tryptamine derivatives containing an allyl group and an aryl sulfonamide unit were designed, synthesized and evaluated for their potential application as anticancer agents. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against HepG2, HeLa, CNE1 and A549 human cancer cell lines. Some of the synthesized compounds showed moderate to good anticancer activities against four selected cancer cell lines, among of which 6ag was found to be the most active analogue possessing IC₅₀ values 16.5–18.7?μM. Further mechanism studies revealed that compound 6ag could significantly induce HepG2 cell cycle arrest at G1 phase, promote cell apoptosis, and inhibit the colony formation as well.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Synthesis and Evaluation of Piperazine-Tethered Derivatives of Alepterolic Acid as Anticancer Agents

Alepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea with potential anti-cancer activity. In this study, alepterolic acid was modified to construct a series of arylformyl piperazinyl derivatives ( 3a – 3p ). The synthesized derivatives were fully characterized with HRMS, NMR, and IR. Four compounds with inhibition rate higher than 30 % at 10 μM ( 3f , 3n , 3g and 3k ) were further measured to obtain the IC₅₀ values against four cancer cell lines, including hepatoma cell lines HepG2, lung cancer cell lines A549, estrogen receptor-positive cell lines MCF7, and triple-negative breast cancer (TNBC) cell lines MDA-MB-231 by MTT assay. It was found that these compounds were more effective to HepG2 and MDA-MB-231 cells, while less toxic to A549 and MCF7 cells, and compound 3n as the most toxic derivatve against MDA-MB-231 cell lines, with IC₅₀ value of 5.55±0.56 μM. Trypan blue staining and colony formation assay showed that compound 3n inhibited the growth of MDA-MB-231 cells and prevented colony formation. Hoechst staining, flow cytometry and western blot analysis revealed that compound 3n induced caspase-dependent apoptosis in MDA-MB-231 cells. Conclusively, compound 3n was demonstrated to be a potential anti-cancer lead compound for further investigation.