Design,synthesis and biological evaluation of novel 2-phenyl-4,5,6,7-tetrahydro-1H-​indole derivatives as potential anticancer agents and tubulin polymerization inhibitors

A new series of 2-phenyl-4,5,6,7-tetrahydro-1H-?indole derivatives as tubulin polymerization inhibitors were synthesized and evaluated for the anti-proliferative activities. All newly prepared compounds were tested for their antiproliferative activity in vitro on the human breast cancer cell line (MCF-7) and human lung adenocarcinoma cell line (A549). Among them, compound 7b with a 4-methoxyl substituent at the phenylhydrazone moiety exhibited the most potent anticancer activity against MCF-7 and A549 with IC₅₀ values of 1.77 ± 0.37 and 3.75 ± 0.11 μM, respectively. Interestingly, 7b displayed significant selectivity in inhibiting cancer cells over LO2 (normal human liver cells). Further mechanism studies revealed that 7b significantly arrested cell cycle at G2/M phase and induced apoptosis in a dose-dependent manner. Additionally, 7b effectively inhibited tubulin polymerization with an inhibitory manner similar to that of colchicine. Furthermore, molecular docking study suggested that 7b had high binding affinities for the colchicine binding pocket of tubulin. Hence, this study demonstrates for the first time that tetrahydroindole can be used as a functional group for the design and development of new tubulin polymerization inhibitors.     

Synthesis of palladium–biscarbene complexes derived from 1,1′-methylenebis(1,2,4-triazole) functionalized in the methylene bridge

Palladium–biscarbene complexes derived from N,N′-bis(1,2,4-triazol-1-yl)methane, which bear an alkyl chain functionalized with a hydroxyl group, have been synthesized ([Pd(L1)Br₂] (6) and [Pd(L1)I₂] (7) [L1 = 1,1′-(3-hydroxypropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)]). Each product is obtained as a non-equimolecular mixture of two conformers. The hydroxyl group has been replaced by bromide and methanesulphonate and ( [Pd(L2)Br₂] [L2 = 1,1′-(3-bromopropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (9)) and ([Pd(L3)Br₂] [L3 = 1,1′-(3-methanesulphonyloxypropylidene)-bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (10)) were obtained, respectively, as mixtures of conformers. All compounds consist of a six-membered metallacyclic structure in a boat conformation. Major conformers present the functionalized chain in the axial position, while in minor conformers it is located in the equatorial position.     

The intermediary RTeI as a source of new TeII and TeIV iodides by addition of (PyH)I and KI: Synthesis and structural features of [{RTeI}{RTeI3}]n, [R2Te−TeIR], (PyH)[RTeI2] and (PyH)n[RTeI(μ-I)TeIR]n (R = 2,6-dimethylphenyl; Py = pyridine)

(DmephTe)₂ (dmeph = 2,6-dimethylphenyl) reacts with resublimed iodine or with pyridinium iodide under Ar atmosphere to yield [{RTeI}{RTeI₃}]_n (1), [R₂Te?TeIR] (2), (PyH)[RTeI₂] (3) and (PyH)_n[RTeI(μ-I)TeIR]_n (4) (R = dmeph; Py = pyridine). While mesityl species analogue to 2 and 3 have been already described, the compounds 1 and 4 represent the first organotellurium iodides of their classes reported. In compound 4 a symmetrical, covalent iodine bridge links two RTeI groups, attaining single [RTeI(μ-I)TeIR] anions connected by Te?I secondary bonds and stabilized by pyridinium cations.     

Antioxidant and α-Glucosidase Inhibitory Compounds of Centella Asiatica

Centella asiatica, as known as Pegagan was previously reported to have anti-hyperglycemic effects in animal diabetic model rats. However, its α-glucosidase activity in vitro assay not yet reported. Our goal in this study is to isolate and identify active compounds as α-glucosidase inhibitor and antioxidant from aqueous ethanol 70% (v/v) extract of C. asiatica. The extract was partitioned by n-hexane, EtOAc, and n-butanol sequentially. Among the fractions tested, EtOAc fraction was showed the highest antioxidant and α-glucosidase inhibitory activities with an IC₅₀ values of 45.42 and 73.17 μg/mL, respectively. The antioxidant activity was conducted by determination of DPPH radical scavenging activity, whereas α-glucosidase inhibitory activity was determined against yeast α-glucosidase. Furthermore, isolation of the ethyl acetate extract yielded two active compounds, which were identified as kaempferol (1) and quercetin (2). Both of the compounds showed good yeast α-glucosidase inhibitory activity with IC₅₀ values of 16.50 and 21.61 μg/mL, respectively. In addition those compounds also could scavenge DPPH radical activity with IC₅₀ values of 9.64 and 11.97 μg/mL, respectively. Due to its ability in reducing α-glucosidase activity and scavenging free radical activity, the C. asiatica appears to be a potential as a good resource for future development of antioxidant and antidiabetic drug.     

Synthesis,characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study

Two series of novel bis(indole) analogues viz., N′-((5-substituted-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)alkanehydrazides (7a–f) and N′-((5-substituted-1-(3-methylbut-2-enyl)-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)acetohydrazide (8a–f) were synthesized and characterized by spectral analysis. The target molecules were screened for their antimicrobial, anticancer activities and structure and activity relationship (SAR) was investigated. Compounds 7a, 7c and 8a were found to be active in antimicrobial screening. Anticancer screening reveals that Compound 7c was active against HeLa cell line with an IC₅₀ of 43.1 μM and compound 7d was found to be interesting candidate with an IC₅₀ of 26.0 and 30.2 μM against Colo-205 and Hep G2 cell lines respectively.     

Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-d-hexosaminidase and chitinase

Insect chitinase and N-acetyl-β-d-hexosaminidases (Hex) are potential targets for developing new pesticides. Here, a series of thiazolylhydrazones I (with substituted group R₁ at N3) and II (with substituted group R₁ at N2) were designed, synthesised and evaluated as competitive inhibitors of OfHex1 and OfChi-h, from the agricultural pest Ostrinia furnacalis. Derivatives I-3d and II-3d, with phenoxyethyl group at R₁, demonstrated the best inhibitory activities against OfHex1 and OfChi-h. Molecular docking analysis indicated that the branched conformation compound II-3d (K_i = 1.5 μmol/L) formed more hydrogen bonds with OfHex1 than the stretched conformation compound I-3d (K_i = 5.9 μmol/L). The differences in compounds’ binding conformations with OfChi-h explained differences in inhibitory activity of compounds I-3d (K_i = 1.9 μmol/L) and II-3d (K_i = 4.1 μmol/L). This work suggests a novel scaffold for developing specific Hex and Chi-h inhibitors.     

New transition metal sulfates templated by 1,4-butanediamine, (C4H14N2)[MII(H2O)6](SO4)2·4H2O (MII: Co,Ni): Structure,reactivity and thermal decomposition

Two new hybrid materials, (C₄H₁₄N₂)[M^II(H₂O)₆](SO₄)₂·4H₂O (M^II: Co (I), Ni (II)), have been synthesised by slow evaporation method at room temperature and crystallographically characterized. They crystallise isotypically in the monoclinic system, space group P2₁/n, with the following unit-cell parameters a = 9.2285(3), b = 11.3333(4), c = 10.6693(4) Å, β = 109.004(2)°, Z = 2 and V = 1055.07(6) Å³ for I and a = 9.2127(2), b = 11.3182(2), c = 10.6434(2) Å, β = 109.094(1)°, Z = 2 and V = 1048.74(4) Å³ for II. The structure of the two supramolecular compounds consists of metallic cation octahedrally coordinated to six water molecules, sulfate anions, 1,4-butanediammonium cation and water molecules linked together via two types of hydrogen bonds, O–H?O and N–H?O. The two compounds are not stable at room temperature and their partial dehydration depends on the humidity of the environment. The thermal decomposition of precursors, studied by thermogravimetric analysis (TG) and temperature-dependent X-ray diffraction (TDXD), shows successive intermediate hydrates and crystalline anhydrous compounds upon dehydration.     

A new molecular building blocks: Synthesis,crystal structure,magnetic and spectroscopic properties of Cu(II) and Ni(II) macrocyclic complexes

New higly unsaturated macrocyclic building blocks [CuLSCN]·ClO₄ (1) (L = N-dl-5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene) and [NiL(SCN)₂] (2) (L = N-dl-5,12-dimethyl-7,14-diisopropyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene) were synthesized and the crystal structures of both compounds were determined. Both complexes crystallizes in monoclinic, space group P2₁/n (1) and P2₁/c (2). Their magnetic properties were studied over the temperature range 1.8–300 K using a Quantum Design SQUID magnetometer (MPMSXL-5-type). The results indicate that both compounds behave as weakly interacting paramagnetic centers in the crystal lattice. The effects of hydrogen bond mediating the magnetic exchange interactions on the spin density have been evidenced by DFT calculations. The NIR–Vis–UV diffuse-reflectance electronic spectra confirm the square pyramidal and octahedral geometry around Cu²⁺ and Ni²⁺ metal ions.     

Molecular spin ladders self-assembly from [Ni(dmit)2]− building blocks: Syntheses,structures and magnetic properties

Two ion-pair compounds, consisting of 1-(4′-R-benzyl)pyridinium ([RBzPy]⁺, R = NO₂ (1) and Br (2)) and [Ni(dmit)₂]⁻ (dmit²⁻ = 2-thioxo-1,3-dithion-4,5-dithiolato), have been synthesized and structurally characterized. The anions of [Ni(dmit)₂]⁻ stack into dimers, which further construct into two-leg ladder through terminal S⋯S interactions in 1, lateral S⋯S interactions in 2. The weak H-bonding interactions of C–H⋯S were observed in 2, while only weak van de Waals interactions between anion and cations in 1. The magnetic susceptibilities measured in 2–300 K indicate AFM exchange interaction domination both two compounds. A peculiar magnetic transition at ∼100 K was observed in 1. An AFM ordering below ∼11 K was found in 2, and the best fit to magnetic susceptibility above 45 K in this compound, using a dimer model with s = 1/2, give rise to Δ/k_B = 36.1 K, zJ = −0.91 K, C = 3.2 × 10⁻³ emu K mol⁻¹ and χ₀ = −4.0 × 10⁻⁶ emu mol⁻¹ with g of 2.0 fixed.     

Looking glass inhibitors: both enantiomeric N-benzyl derivatives of 1,4-dideoxy-1,4-imino-d-lyxitol [a potent competitive inhibitor of α-d-galactosidase] and of 1,4-dideoxy-1,4-imino-l-lyxitol [a weak competitive inhibitor of α-d-galactosidase] inhibit naringinase,an α-l-rhamnosidase competitively

Benzhydryl protection by diphenyldiazomethane of an alcohol in enantiomeric base-sensitive ribonolactones allows short efficient syntheses of 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) and of 1,4-dideoxy-1,4-imino-l-lyxitol (LIL). DIL showed potent [K_i = 0.13 μM]—and LIL showed weak [K_i = 113 μM]—competitive inhibition of α-d-galactosidase. Both enantiomers N-benzyl-DIL [K_i = 64 μM] and N-benzyl-LIL [K_i = 13 μM] were moderate competitive inhibitors of naringinase, an α-l-rhamnosidase.     

Chiral 1,4-morpholin-2,5-dione derivatives as α-glucosidase inhibitors: Part 2

A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, diastereomeric monolactim ethers derived from l-valine. The compounds investigated, were inactive toward β-glucosidase, α-mannosidase and α-galactosidase but behave as noncompetitive inhibitors against the α-glucosidase (from Saccharomices cervisiae) with some showing a good inhibition ability (0.05 < K_i < 0.18 mM).     

anti-Tuberculosis natural products: synthesis and biological evaluation of pyridoacridine alkaloids related to ascididemin

There is an urgent need for novel therapeutics possessing new modes of action to treat tuberculosis (TB) infections. In this study we report on the synthesis and biological evaluation of a series of pyrido[2,3,4-kl]acridin-6-one alkaloids related to the anti-TB (MIC 0.35 μM) but cytotoxic (IC₅₀ <0.14 μM) marine natural product ascididemin (1). The most interesting compounds identified were 21 and 24, which were found to inhibit the growth of Mycobacterium tuberculosis (Mtb) H₃₇Rv with MIC 2.0 μM, but with negligible cytotoxicity towards Vero and P388 cells (IC₅₀>25 μM). Another analogue (10) was evaluated against a range of singly-drug-resistant strains of Mtb and was found to exhibit no cross-resistance. These results suggest that the pyrido[2,3,4-kl]acridin-6-one skeleton may provide a useful scaffold for future studies directed towards possible anti-TB drugs.     

Synthesis of some Mannich base derivatives and their antimicrobial activity study

A series of 2-(phenyl)-2-(morpholin-4-yl)-N-phenylacetamide I–VII were synthesized by Mannich base method. Synthesized compounds I–VII were confirmed by IR, ¹H NMR, ¹³C NMR, mass and elemental analyses. Synthesized compounds I–VII were screened for antibacterial activity against various bacterial strains and compared with standard Ciprofloxacin at concentration 100 μg/mL and for antifungal activity against various fungal strains and compared with Clotrimazole at concentration 100 μg/mL; particularly 3-(4-chlorophenyl)-3-(morp holin-4-yl)-N-phenylpropanamide lll that has high antibacterial activity against Streptococcus epidermidis was compared with standard Ciprofloxacin.     

Cytotoxic arylbenzofuran and stilbene derivatives from the twigs of Artocarpus heterophyllus

Four new natural products, including three arylbenzofurans named heterophyllenes A-C (1–3), and one stilbene named heterophyllene D (4), together with twenty-one known compounds were isolated from the twigs of Artocarpus heterophyllus and their structures elucidated by spectroscopic methods, mainly 1D and 2D NMR spectroscopy. The cytotoxic activity of selected compounds against KB, MCF-7 and NCI-H187 cell lines was evaluated. Heterophyllene C (3) exhibited cytotoxicity against the MCF-7 cell line with an IC₅₀ value of 12.56 μM. Additionally, the known compounds norartocarpin and artocarpin showed cytotoxic activity against MCF-7 and KB cell lines with IC₅₀ values of 10.04 and 13.57 μM, respectively. Both compounds also displayed cytotoxicity against the NCI-H187 cell line with values of 14.78 and 14.21 μM, respectively.     

Organo-aluminum,zinc and magnesium derivatives of the imidotris(amido)phosphate Me3SiNP(NHtBu)3

Reactions of (^tBuHN)₃PNSiMe₃ (1) with the alkyl-metal reagents dimethylzinc, trimethylaluminum and di-n-butylmagnesium yield the monodeprotonated complexes [MeZn{(N^tBu)(NSiMe₃)P(NH^tBu)₂}] (2), [Me₂Al{(N^tBu)(NSiMe₃)P(NH^tBu)₂}] (3) and [Mg{(N^tBu)(NSiMe₃)P(NH^tBu)₂}₂] (4), respectively. Attempts to further deprotonate complex 2 with n-butyllithium or di-n-butylmagnesium result in nucleophilic displacement of the methylzinc fragment by lithium or magnesium. The two remaining amino protons of 3 are removed by reaction with di-n-butylmagnesium to give a heterobimetallic complex in which the coordination sphere of magnesium is completed by two molecules of THF (5 · 2THF) or one molecule of TMEDA (5 · TMEDA). Reaction of complex 3 with 1 equiv. of n-butyllithium followed by treatment of the product with di-n-butylmagnesium yields the complex {Me₂Al[(N^tBu)(NSiMe₃)P(N^tBu)₂]MgBu} Li · 4THF (6 · 4THF), the first example of a triply deprotonated complex of 1 containing three different metals. Reaction of complex 5 with iodine results in cleavage of an Al–Me group to give {MeIAl[(N^tBu)(NSiMe₃)P(N^tBu)₂Mg]} (7). Complexes 5 · 2THF, 5 · TMEDA, 6 · 4THF and 7 have been characterized in solution by multinuclear (¹H, ¹³C, ³¹P and ⁷Li) NMR spectroscopy, while the solid-state structures of 2, 4 and 5 · 2THF have been determined by X-ray crystallography.     

Stereoselective synthesis of novel tetrahydroxypyrrolizidines

N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-l-ribose 12a has been converted into (1R,2S,6R,7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7-tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1,2,6,7-tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold (7: IC₅₀=130 μM, K_i=120 μM; 8: IC₅₀=200 μM, K_i=180 μM, mixed type of inhibition).     

Two-dimensional molecular magnets based on [Pt(mnt)2]− ions: Structures and magnetic properties

Two compounds of composition [FBzPy][Pt(mnt)₂] (1) and [FBzPy][Pt(mnt)₂] · 0.25-MeCN (2) ([FBzPy]⁺ = 1-(4′-fluorobenzyl)pyridinium and mnt²⁻ = maleonitriledithiolate) were prepared and their crystal structures were determined. The solvent molecule, MeCN, incorporated into lattice leads the anionic stacking pattern to be distinct between 1 and 2. The regular anionic stacking columns are connected by the anionic dimers to construct into 2D anionic networks in 1, while the anionic fourfold subunit develop into anionic layers though lateral S⋯S interactions in 2. As for two compounds, the magnetic susceptibilities in 2–350 K were measured, and the magnetic exchange schemes were built based on the analyses both crystal structures and extended Hückel molecular orbital calculations. The magnetic coupling model of an alternating AFM Heisenberg chain with an isolated AFM coupling dimer was dealt with 1, while a spin dimer with s = 1/2 with 2, and the magnetic coupling parameters were further gained via simulating the temperature dependent magnetic susceptibility data of two compounds.     

Design,synthesis and molecular modeling studies of few chalcone analogues of benzimidazole for epidermal growth factor receptor inhibitor in search of useful anticancer agent

In the present investigation, few 3-(substitutedphenyl)-1-[2-(1-hydroxy-ethyl)]-1H-benzimidazol-1-yl)prop-2-en-1-ones are EGFR antagonist are designed, by molecular docking analysis. The synthesized compounds were tested for their in vitro anticancer activity by propidium iodide fluorescent assay and Trypan blue viability assay against colorectal cancer cell lines (HCT116) and non-small cell lung cancer cell lines (H460). Human Epithelial Kidney cell lines (HEK) are used as normal cell lines for studying effect of drug on non-cancerous cells within human body. Evaluation of cytotoxic studies of synthesized compounds CHL(1–8) reveal that compound CHL1 [IC₅₀ = 7.31 and 10.16 μM against HCT116 and H460 cell lines respectively, by PI assay] and CHL8 [IC₅₀ = 12.52 and 6.83 against HCT116 and H460 μM cell lines respectively] possess promising cytotoxic activity.     

Copper(I) complexes of heterocyclic thiourea ligands

The coordination of heterocyclic thiourea ligands (L = N-(2-pyridyl)-N′-phenylthiourea (1), N-(2-pyridyl)-N′-methylthiourea (2), N-(3-pyridyl)-N′-phenylthiourea (3), N-(3-pyridyl)-N′-methylthiourea (4), N-(4-pyridyl)-N′-phenylthiourea (5), N-(2-pyrimidyl)-N′-phenylthiourea (6), N-(2-pyrimidyl)-N′-methylthiourea (7), N-(2-thiazolyl)-N′-methylthiourea (8), N-(2-benzothiazolyl)-N′-methylthiourea (9), N,N′-bis(2-pyridyl)thiourea (10) and N,N′-bis(3-pyridyl)thiourea (11)) with CuX (X = Cl, Br, I, NO₃) has been investigated. CuX:L product stoichiometries of 1:1–1:5 were found, with 1:1 being most common. X-ray structures of four 3-coordinate mononuclear CuXL₂ complexes (CuCl(6)₂, CuCl(7)₂, CuBr(6)₂, and CuBr(9)₂) are reported. In contrast, CuBr(1)₂ is a 1D sulfur-bridged polymer. CuIL structures (L = 7, 8) are 1D chains with corner-sharing Cu₂(μ-I)₂ and Cu₂(μ-S)₂ units, and CuCl(10) is a 2D network having μ-Cl and N-/S-bridging L. Two [CuL₂]NO₃ structures are reported: a mononuclear 4-coordinate copper complex with chelating ligands (L = 10) and a 1D link-chain with N-/S-bridging L (L = 3). Two ligand oxidative cyclizations were encountered during crystallization. CuI crystallized with 6 to produce zigzag ladder polymer [(CuI)₂(12)]·½CH₃CN (12 = N-(pyrimidin-2-yl)benzo[d]thiazol-2-amine) and CuNO₃ crystallized with 10 to form [Cu₂(NO₃)(13)₂(MeCN)]NO₃ (13 = dipyridyltetraazathiapentalene).     

Novel benzoxazole-based thiosemicarbazide derivatives as new inhibitors of urease and β-Glucuronidase: Synthesis,in vivo anti-nematodal activity and ADMET prediction along with in silico study

Here, we discuss the synthesis of thiosemicarbazide derivatives based on benzoxazole. These compounds were obtained via sequence of reactions. The targeted products were confirmed using a number of spectroscopic methods, including NMR (1H and 13C) and EI-MS. After spectral confirmation all the synthesized compounds were evaluated for urease and β-Glucuronidase inhibitory activity in order to explore their biological significances in the presence of standard drug thiourea (IC₅₀ = 21.86 ± 0.40) and D-saccharic acid 1,4-lactone (IC50 value 22.00 ± 1.10 µM) respectively. Among the evaluated series, compounds 14 and 15 (1.10 and 0.01 and 2.20 and 0.60) were shown to have slightly greater potential than standard drugs. Anti-nematodal activity was also employed to explore the cytotoxic nature of synthesized analogs. In order to establish the binding relationship with enzyme active sites, molecular docking experiments were done and directions for compound modification based on SAR features were addressed. In addition, ADMET prediction study also investigated to found drug like properties of the potential analogs.