Synthesis and structure–activity relationships of novel furazan-3,4-diamide analogs as potent anti-cancer agents

This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.     

Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.     

Synthesis and anticancer activity of novel quinoline–docetaxel analogues

A series of novel quinoline–docetaxel analogues (6a–6g, 13a–13g) were designed and synthesized by introducing bioactive quinoline scaffold to C2′-OH of docetaxel. The anticancer activities of these novel analogues were investigated against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound 6c was found to be the most potent one, and its IC₅₀ value against MCF-7-MDR was 8.8 nM (IC₅₀ of docetaxel was 180 nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce drug-resistance.     

Synthesis and structure–activity relationship of p-carborane-based non-secosteroidal vitamin D analogs

1α,25-Dihydroxyvitamin D₃ [1α,25(OH)₂D₃: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non-secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure–activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure–activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications.     

Synthesis and anti-parasitic activity of a novel quinolinone–chalcone series

A series of novel quinolinone–chalcone hybrids and analogues were designed, synthesized and their biological activity against the mammalian stages of Trypanosoma brucei and Leishmania infantum evaluated. Promising molecular scaffolds with significant microbicidal activity and low cytotoxicity were identified. Quinolinone–chalcone 10 exhibited anti-parasitic properties against both organisms, being the most potent anti-L. infantum agent of the entire series (IC₅₀ value of 1.3 ± 0.1 μM). Compounds 4 and 11 showed potency toward the intracellular, amastigote stage of L. infantum (IC₅₀ values of 2.1 ± 0.6 and 3.1 ± 1.05 μM, respectively). Promising trypanocidal compounds include 5 and 10 (IC₅₀ values of 2.6 ± 0.1 and 3.3 ± 0.1 μM, respectively) as well as 6 and 9 (both having IC₅₀ values of <5 μM). Chemical modifications on the quinolinone–chalcone scaffold were performed on selected compounds in order to investigate the influence of these structural features on antiparasitic activity.     

Synthesis and structure–activity relationships of novel benzofuran farnesyltransferase inhibitors

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC₅₀ = 1.1 nM) and antitumor activity in human cancer xenografts in mice.     

Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs

Hybrid bisindole-thiosemicarbazides analogs (1–18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC₅₀ values ranging from 0.1 to 5.7 μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC₅₀ values ranging from 7.12 to 15.0 μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC₅₀ values 33.2 ± 0.75, 21.4 ± 0.30 and 28.12 ± 0.25 μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds.     

In vitro structure–activity relationships of aplysinopsin analogs and their in vivo evaluation in the chick anxiety–depression model

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT_2B and 5-HT_2C receptor subtypes, with selectivity for 5-HT_2B over 5-HT_2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with K_i’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.     

Synthesis and structure–activity relationship study of novel quinazolinone-based inhibitors of MurA

MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure–activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC₅₀ of 8 µM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1 µg/mL to 8 µg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance.     

Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH₂ group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.     

Synthesis,single crystal and antitumor activities of benzimidazole–quinazoline hybrids

A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by ¹H and ¹³C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.     

Synthesis and structure–activity relationships of novel indazolyl glucocorticoid receptor partial agonists

SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors.     

Synthesis of new analogs of benzotriazole,benzimidazole and phthalimide—potential inhibitors of human protein kinase CK2

New derivatives of 4,5,6,7-tetrabromo-1H-1,2,3-benzotriazole (TBBt), 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi), and N-substituted tetrabromophthalimides were synthesized and their effect on the activity of human protein kinase CK2 was examined. The most active were derivatives with N-hydroxypropyl substituents (IC₅₀ in 0.32–0.54 μM range) whereas derivatives of phthalimide were almost ineffective.     

Synthesis,in vitro structure–activity relationship,and in vivo studies of 2-arylthiazolidine-4-carboxylic acid amides as anticancer agents

A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10 mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60 mg/kg.     

Synthesis,characterization, antimicrobial activity and structure–activity relationships of new aryldisulfonamides

A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33).     

Synthesis and in vitro antikinetoplastid activity of polyamine–hydroxybenzotriazole conjugates

Thirteen new polyamine derivatives coupled to hydroxybenzotriazole have been synthesized and evaluated for their in vitro antikinetoplastid activity. Trypanosoma Trypanothione reductase (TryR) was envisioned as a potential target. Among all tested molecules, only one compound, a N³-spermidine–benzotriazole derivative, displayed relevant inhibitory activity on this enzyme but was not active on parasites. The corresponding Boc-protected spermidine–benzotriazole was however trypanocidal against Trypanosoma brucei gambiense with an IC₅₀ value of 1 μM and was completely devoid of cytotoxicity. On the intramacrophage amastigotes of Leishmania donovani, a N²-spermidine conjugate of this series, exhibited an interesting IC₅₀ value of 3 μM associated with both low cytotoxicity against axenic Leishmania donovani. These new compounds are promising leads for the development of antikinetoplastid agents and their targets have to be deciphered.     

Synthesis and biological evaluation of novel cryptophycin analogs with modification in the β-alanine region

Structure modification of the β-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (β-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.     

Synthesis,characterization and antimalarial activity of quinoline–pyrimidine hybrids

The aim of this study was to synthesize a series of quinoline–pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC₅₀: 0.157 vs 0.417 μM, ～threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.     

Synthesis and in vitro and in vivo evaluation of manganese(III) porphyrin–dextran as a novel MRI contrast agent

5-(4-Aminophenyl)-10,15,20-tris(4-sulfonatophenyl) manganese(III) porphyrin conjugated with dextran was synthesized. Its potential of being used as a tumor-targeting magnetic resonance imaging contrast agent was evaluated in vitro and in vivo. The results demonstrated that the compound has a longitudinal relaxivity (R₁) higher than Gd-DTPA, low cytotoxicity and binding specificity to tumor cell membrane.