Analogs 2a Research Articles

Design and synthesis of novel pyrimido[5,4-d]pyrimidine derivatives as GPR119 agonist for treatment of type 2 diabetes

We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC50 values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC0–2h at the dose of 300 mg/kg.

Anticancer Activity and Catalytic Potential of Ruthenium(II)-Arene Complexes with N,O-Donor Ligands.

The special ability of organometallic complexes to catalyze various transformations might offer new effective mechanisms for the treatment of cancer. Studies that report both the biological properties and the ability of metallic complexes to promote therapeutically relevant catalytic reactions are limited. Herein, we report the anticancer activity and catalytic potential of some ruthenium(II)-arene complexes bearing bidentate Schiff base ligands (2a and 2b) and their reduced analogues (5a and 5b, respectively). In comparison to their Schiff base counterparts 2a and 2b, we demonstrate that amine complexes 5a and 5b display (i) a higher in vitro antiproliferative activity on different human cancer cell lines, (ii) a lower rate of hydrolysis, and (iii) an improved initial catalytic rate for the reduction of NAD+ to NADH. In contrast to their imine analogues 2a and 2b, we also show that amine complexes 5a and 5b induce the generation of intracellular reactive oxygen species (ROS) in MCF-7 breast cancer cells. Our results highlight the impact that a simple ligand modification such as the reduction of an imine moiety can have on both the catalytic and biological activities of metal complexes. Moreover, the ruthenium complexes reported here display some antiproliferative activity against T47D breast cancer cells, known for their cis-platin resistance.

Synthesis and Antimicrobial Evaluation of (1‐(2‐(Benzyloxy)‐2‐oxoethyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl Benzoate Analogues

A convenient one pot synthesis of 20 (1‐(2‐(benzyloxy)‐2‐oxoethyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl benzoate analogues (5a–5t) with ester functionality was carried out via Cu(I) catalyzed click reaction between prop‐2‐yn‐1‐yl benzoates and benzyl 2‐azidoacetates. The structure of synthesized triazoles were explicated by various spectral techniques like FT‐IR, 1H NMR, 13C NMR, and high‐resolution mass spectrometry and evaluated for in vitro antimicrobial potential against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Candida albicans, and Aspergillus niger. Most of synthesized triazole derivatives exhibited average to excellent activity against tested microbial strains.

Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist

A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a–d and 5a–c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists.

Facile Syntheses and Molecular-Docking of Novel Substituted 3,4-Dimethyl-1H-pyrrole-2-carboxamide/carbohydrazide Analogues with Antimicrobial and Antifungal Properties.

The article describes the use of facile one-pot, high-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamides 3a–m and carbohydrazide analogues 5a–l as potential antifungal and antimicrobial agents. The structural identity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compounds 5h, 5i and 5j were found to be the most potent against Aspergillus fumigatus, with MIC values of 0.039 mg/mL. The compound 5f bearing a 2, 6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with a MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking with the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron-related deleterious side effects observed with many existing antifungal compounds.

Dibenzofuran, dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamides as potent inhibitors of Mycobacterium tuberculosis

Herein described the design, synthesis and antitubercular evaluation of novel series of dibenzofuran, dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamide analogs. One pot condensation of N-methyl carbazole, dibenzofuran and dibenzothiophene methyl ketones with thiourea in the presence of Iodine and CuO gave respective 2-aminothiazoles 4–6 in very good yields. Aminothiazoles were further coupled with substituted cinnamic acids using acid-amine coupling conditions to give desired cinnamamide analogs 8a–e, 9a–e and 10a–e. All the newly synthesized compounds were fully characterized by their NMR and mass spectral analysis. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv (Mtb) resulted 8c, 10d and 10e (MIC: 0.78 µg/mL) and 2-aminothiazoles 5 and 6 (MIC: 1.56 µg/mL) as potent compounds with lower cytotoxicity profile.

Synthesis and pharmacological evaluation of combretastatin-A4 analogs of pyrazoline and pyridine derivatives as anticancer, anti-inflammatory and antioxidant agents

Three category of N1-phenyl pyrazoline (5a–e), N1-phenyl-sulfonyl pyrazoline (6a–e), and pyridine analogs (8a–d) of combretastatin-A4 were synthesized. The structures of compounds were verified by spectroscopic techniques. All the compounds were screened for their anticancer activity against MCF-7 cell line, antioxidant (DPPH, NO, SOR and H2O2), and anti-inflammatory activity while compounds (8a–d) additionally tested against K562 cell line. Compounds 8a and 8b showed substantial anticancer activity against MCF-7 cell line (GI50 = 5.59 and 11.70 µM), although not comparable with adriamycin (GI50 ⩽ 0.1 µM). However, none of the compound was active against the K562 cell line. Nevertheless, compound 8a displayed better cytostatic activity (TGI = 69.2 µM) than the standard drug adriamycin (TGI = 75.8 µM). Most of the compounds 5a, 5b, 5c, 5e, 6a, 6b, 6c, 6d, 6e 8a, and 8b have excellently inhibited all of the free radicals better than standard drug ascorbic acid, whereas compound 5c and 5b demonstrated significant anti-inflammatory activity comparable with diclofenac sodium, a standard anti-inflammatory drug.

Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius.

Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyketide-derived molecular halves, followed by oxidative cyclo-condensation. Biomimetic conversion of the co-occurring 4'-O-demethylancistrocladinium A (8a) to ancistrocyclinone A (5) via a quinoid intermediate supported the postulated pathway. Ancistrocyclinone A (5) was found to significantly inhibit the viability of drug-sensitive human leukemia (CCRF-CEM) and multidrug-resistant tumor cells (CEM/ADR5000) with comparable efficacies.

Synthesis, Single Crystal X-Ray, and Anticancer Activity of Some New Thiophene and 1,3-Thiazolidine Derivatives

New series of thiophenes 6a–6e and 1,3-thiazolidines 13a–13f and 15a–15e were synthesized starting from 2-(4-methoxybenzoyl)-3-(phenylamino)-3-thioxopropanoate 3. The reaction of 3 with 1-aryl-2-bromoethanones 4a–4e yielded thiophenes 6a–6e. The X-ray single crystal analysis data accumulated for 6c and its structural features can be extended to the analogues 6a, 6b and 6d, 6e. Treatment of 3 with ethyl 2-bromoacetate afforded 1,3-thiazolidinone 11 which upon treatment with aldehydes 12a-f or isatins 14a–4e gave 5-arylidene derivatives 13a–13f and 4-oxo-5(-2-oxoindolin)-3-ylidenes 15a–15e, respectively. The newly synthesized compounds were tested in vitro for their anti-cancer activity against two cell lines (HepG-2 and MCF-7) using MTT assay. Most of these compounds demonstrated a significant anticancer activity compared with that of doxorubicin. Isatin derivative 15a was the most potent compound against HepG-2 cancer cells whereas p-MeO substituted benzylidine 13b showed the highest anticancer activity against MCF-7 cancer cells. The fluoro substituted isatin 15d showed anticancer activity more potent than doxorubicin against both HepG-2 and MCF-7 cancer cells, respectively.

Synthesis, biological evaluation, and molecular docking of ropivacaine analogs as local anesthetic agents

Two series of ropivacaine analogs (4a–4q, 7a–7c) were synthesized, and their biological activities were evaluated as local anesthetic agents. Most of the compounds displayed detectable local anesthetic characteristics. Among them, compound 4l showed significant efficacy with sciatic nerve block, infiltration, corneal surface, and spinal anesthetic activities. It was as potent as the reference compound ropivacaine. Dissociation constants of these compounds were 5.9–7.9. In addition, molecular docking modeling on compound 4l and ropivacaine was performed to delineate structural requirements and potential mechanisms for the local anesthetic activity. This study provides valuable new information for our ongoing endeavor to design more potent local anesthetics.

Synthesis of 14-deoxy-11,12-didehydroandrographolide analogues as potential cytotoxic agents for cholangiocarcinoma

A series of 14-deoxy-11,12-didehydroandrographolide analogues were synthesized from naturally occurring andrographolide and their cytotoxicity evaluated against nine cancer cell lines including cholangiocarcinoma. Analogues 5a and 5b exhibited the most potent cytotoxicity with ED50s of 3.37 and 3.08 μM on KKU-M213 cell lines and 2.93 and 3.27 μM on KKU-100 cell lines, respectively. Selective cytotoxicity on cholangiocarcinoma cell lines identified in this study highlight the importance of structural modification in the development of drugs for this cancer.

Vitamin D Analogues with a p-Hydroxyphenyl Group at the C25 Position: Crystal Structure of Vitamin D Receptor Ligand-Binding Domain Complexed with the Ligand Explains the Mechanism Underlying Full Antagonistic Action.

Vitamin D receptor (VDR) antagonists can be classified into two categories: the first category of VDR antagonists, which do not stabilize the helix 11-12, and the second category of antagonists, which destabilize the helix 6-7 region. To elucidate the mechanism underlying the first category antagonists by using the crystal structure, we designed and synthesized several VDR ligands with a p-hydroxyphenyl group at the C25-position. Of these, 22S-butyl-25-carbonyl analogue 5b and 25-di-p-hydoroxyphenyl analogues 6a,b showed strong antagonistic activity. We succeeded in cocrystallizing the ligand-binding domain of VDR complexed with 5b and found that the structure showed an alternative conformation of the helix 11-12 that explained the mechanism of the first category antagonists. Taking the present and previous studies together, we could elucidate the mechanisms underlying first and second categories antagonists based on individual crystal structures. This study provides significant insights into antagonism against not only VDR but also nuclear receptors.

Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H⁺)-ATPase Inhibitors.

The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I–IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a–e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC50 = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment.

Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model

A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC50 values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.

Synthesis, characterization and biological evaluation of some new indomethacin analogs with a colon tumor cell growth inhibitory activity

Focusing particularly on colorectal cancer, and suggesting research strategies that may help to accelerate the future clinical application of indomethacin for the treatment of cancer, the molecular structures of indomethacin was used as starting scaffold to design novel amide analogs, and the effects of those analogs on the proliferation of human cancer cells were evaluated against three colon cancer cell lines, namely, HCT-116, CACO-2, and HT-29. Compared to indomethacin, the new derivatives displayed significantly increased activities. Interestingly two of the indomethacin analogs 7a and 8c displayed high growth inhibitory activity in nano-molar to micro-molar range against all three human colon cancer cell lines with IC50 values ranging from 0.055 to 4.0 µg/ml compared to 0.7–5.45 µg/ml for 5-fluorouracil (5-FU). Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds 7a and 8c on the HT-29 and HCT-116 cell lines respectively were studied. The results indicated that compounds 7a and 8c arrested the cell cycle at G1/S and G0/G1 phase in HT-29 and HCT-116 cells respectively and might induced apoptosis via caspase-3 dependent pathway.

Synthesis and evaluation of novel urea and amide derivatives of 2-amino-4-phenylthiazole as potential antibacterial agents

Two series of novel urea- and amide-functionalized 2,4-disubstituted thiazole derivatives were efficiently synthesized and characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The target compounds were evaluated for their in vitro antibacterial activity against four bacterial strains, including Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa. The results revealed that the thiazolyl-N-substituted amide derivatives 3a–i showed better antibacterial activity compared with those corresponding substituted phenyl thiazolyl urea analogs 4a–i. The compounds 3a–i were particularly active against gram-positive bacteria. Compounds 3f, 3g, and 4g displayed the potent antibacterial activity. Based on structure–activity relationships studies, we observed that the presence of halogen groups such as chloro or fluoro enhanced the antibacterial activity of newly synthesized compounds.

Succinamide derivatives of melampomagnolide B and their anti-cancer activities

A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a–3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a–4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d–3i and dimers 4f–4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28 to 33.5µM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50=280–980nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c–3l and 4b–4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h–3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1–8.1μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1–109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control.

Synthesis and biological evaluation of new 2-(6-alkyl-pyrazin-2-yl)-1H-benz[d]imidazoles as potent anti-inflammatory and antioxidant agents

A novel series of 2-(6-alkyl-pyrazin-2-yl)-1H-benzo[d]imidazole analogs (3a–3j) derived from 2-(6-chloropyrazin-2-yl)-1H-benzo[d]imidazole (2) by reacting with various substituted cyclic and acyclic secondary amines in presence of Pd-PEPPSI Mes catalyst by using Buchwald–Hartwig amination in excellent yield. The structures of newly synthesized compounds were elucidated by Fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance, 13C-nuclear magnetic resonance, electrospray ionisation mass spectrometry and high-resolution mass spectrometry spectral data. All the title compounds (3a–3j) were evaluated for in vitro screening against cyclooxygenase-1 and cyclooxygenase-2 by colorimetric COX (human ovine) inhibition assay and in vivo anti-inflammatory activity against cyclooxygenase-2 enzyme by means of the carrageenan-induced rat paw edema. The compound 3i was found to have potent anti-inflammatory activity than standard Ibuprofen. The compounds 3a, 3e, and 3j showed appreciable activity against cyclooxygenase-2 enzyme. However the compounds 3a, 3e, 3g, 3h, and 3j were showed maximum activity within 15 to 24 h and 3g and 3i were showed good DPPH scavenging activity. Moreover, the docking studies were also performed and the results are well agreement with the biological data, suggested that compound 3i was a potential anti-inflammatory agent for further development.

Ferrocenyl and organic novobiocin derivatives: Synthesis and their in vitro biological activity

A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.

Dyes derived from benzo[ a ]phenoxazine – synthesis, spectroscopic properties, and potential application as sensors for l ‐cysteine

Several benzo[a]phenoxazine dyes containing a maleimide moiety have been synthesised and characterised by proton nuclear magnetic resonance spectroscopy and mass spectrometry. The spectroscopic properties, such as absorption and emission spectra, of these dyes – 9-maleimido-5H-benzo[a]phenoxazin-5-one (7a), 6-chloro-9-maleimido-5H-benzo[a]phenoxazin-5-one (7b), and 6-bromo-9-maleimido-5H-benzo[a]phenoxazin-5-one (7c) – were examined. These compounds were evaluated as potential fluorescent and colorimetric probes for the detection of biothiols. Results show that the studied compounds exhibit colorimetric and fluorescent responses to l-cysteine at pH 7.4. In the presence of l-cysteine, the fluorescence intensity of synthesised dyes is greatly enhanced. The addition of l-cysteine to solutions of dyes 7a to 7c also results in red shifts of their absorption bands. The cytotoxic effect of tested dyes 7a to 7c against human neuroblastoma cells (SH-SY5Y) was determined by MTT assay. The fluorescent response of these compounds to thiols SH-SY5Y was examined. The results show that the tested compounds exhibit fluorescent response in this cell line, and the benzo[a]phenoxazine dyes substituted in the 6-position with a halogen (7b and 7c) are less toxic against cells under experimental conditions than their unsubstituted analogue (7a).