Synthesis of nitrogen-containing monoterpenoids with antibacterial activity

Abstract

Incorporation of the Beckmann rearrangement into the presented research resulted in the formation of nitrogen-containing terpenoid derivatives originating from naturally occurring compounds. Both starting monoterpenes and obtained derivatives were subjected to estimation of their antibacterial potential. In the presented study, Staphylococcus aureus was the most sensitive to examined compounds. The Minimal Inhibitory Concentration (MIC) experiments performed on S. aureus demonstrated that the (?)-menthone oxime (?)-8 and (+)-pulegone oxime (+)-13 had the best antibacterial activity among the tested derivatives and starting compounds. Their MIC₉₀ value was 100?µg/mL. The obtained derivatives were also evaluated for their inhibitory activity against bacterial urease. Among the tested compounds, three active inhibitors were found – oxime 14 and lactams (?)-15 and 16 limited the activity of Sporosarcina pasteurii urease with K_i values of 174.3?µM, 43.0?µM and 4.6?µM, respectively. To our knowledge, derivative 16 is the most active antiureolytic lactam described to date.     

Synthesis and biological activity evaluation of new thiazolidinone-diclofenac hybrid molecules

Abstract

A novel series of [2-(2,6-dichlorophenylamino)-phenyl]-acetic acid N`-3-(substituted)-4-thiazolidin-5-ylidenemethyl-hydrazide derivatives has been designed and synthesized. The structures of synthesized compounds were confirmed by their <sup>1</sup>H NMR, <sup>13</sup>C NMR and LCMS spectroscopic data. Target compounds were screened for their in vitro anticancer activity according to US NCI protocols, in vitro trypanocidal activity toward Trypanosoma brucei brucei (Tbb) and evaluated for anti-inflammatory activity on the carrageenan edema model in rats. Biological screening data led to identification of compounds 3.3 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-hydrazide) and 3.7 ([2-(2,6-dichloro-phenylamino)-phenyl]-acetic acid N`-(4-oxo-2-thioxo-3-(3-trifluoromethylphenyl)thiazolidin-5-ylidenemethyl)-hydrazide) which demonstrated moderate antitumor activity on the non-small-cell lung cancer NCI-H522 and colon cancer HCT-116 cell lines. Several hit compounds (3.2, 3.4) exhibited the promising and significant inhibition growth of the parasites at micromolar concentrations (IC₅₀ values of 4.8 and 7.06?μM, respectively). The synthesized compounds also demonstrated considerable anti-inflammatory effect comparable to the reference non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac sodium or ketorolac tromethamine.     

Excelsanone,a new isoflavonoid from Erythrina excelsa (Fabaceae), with in vitro antioxidant and in vitro cytotoxic effects on prostate cancer cells lines

Abstract

A new isoflavonoid, excelsanone (2), was isolated from the ethyl acetate extract of Erythrina excelsa stem bark, together with three known compounds namely 6,8-diprenylgenistein (3), β-sitosterol (1) and sitosteryl-β-D-glucopyranoside (4). Their structures were elucidated using spectroscopic methods (HR-ESI-MS, NMR and IR) and by comparison with some literature data. The antioxidant activity of crude extracts and two isolated compounds was evaluated using free radical scavenging (DPPH) and Ferric Reducing Ability Power (FRAP) methods with catechin as standard. The results of the radical scavenging activity showed that excelsanone (2) has a moderate potential with an IC₅₀ of 1.31?mg/ml. The cytotoxicity of compounds 2 and 3 as well as the ethyl acetate extract was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two prostate cancer cell lines (DU145 and PC3). Excelsanone (2) induced a greater cytotoxicity in all tested cell lines, with a significant inhibition of DU145 cells growth in a concentration-dependent manner.     

An efficient multicomponent synthesis and in vitro anticancer activity of dihydropyranochromene and chromenopyrimidine-2,5-diones

A series of dihydropyranochromenes and chromenopyrimidine-2,5-diones having chromene scaffold were synthesized via efficient multicomponent protocol in aqueous β-cyclodextrin. The reaction is free of toxic solvents, operating under mild conditions and allows for ease of product isolation, making it more environmentally friendly. All the synthesized compounds biologically evaluated for their potential inhibitory effect on both cervical cancer cell line (HeLa) and human breast adenocarcinoma cell line (MCF-7). Of these compounds, 4d was found to be the most potent inhibitors of HeLa and MCF-7 demonstrating IC₅₀ values of 19?µM and 7?µM. Compounds 4b, 4e and 4f also shown significantly good in vitro anticancer activity against HeLa and MCF-7 cancer cell lines.     

Facile synthesis of highly functionalized novel pyrazolopyridones using oxoketene dithioacetal and their anti-HIV activity

A series of novel 3-amino-4,5-dihydro-6-methyl-4-oxo-N-aryl-1H-pyrazolo[4,3-c]pyridine-7-carboxamide have been synthesized starting from various oxoketene dithioacetals. The cyclocondensation reaction of 2-(bis(methylthio)methylene)-3-oxo-N-arylbutanamide 2a–w with cyanoacetamide using NaOiPr as base under reflux condition afforded novel highly functionalized pyridone 3a–w derivatives. Further, [3?+?2] cyclocondensation reaction of pyridones with hydrazine in the presence of alcohol was yielded pyrazolopyridones (23 nos) 4a–w with excellent yields. All newly synthesized compounds were evaluated for in vitro anti-HIV activity using MTT method. Most of these compounds have showed moderate to potent activity against HIV-1 (III_B) and HIV-2 (ROD) strains with an IC₅₀ ranging from >18 IC₅₀[µg/ml] to <100 IC₅₀[µg/ml]. Among them, compounds 4j and 4v were identified as the most promising compound for both types of HIV strains. (IC₅₀?=?18?µg/ml). Three compounds 4l, 4m, and 4p have been found potent anti-HIV 1 and 2 activity against MT-4 cells.     

In vitro cytotoxicity evaluation of thiourea derivatives bearing Salix sp. constituent against HK-1 cell lines

Abstract

In searching for drugs from natural product scaffolds has gained interest among researchers. In this study, a series of twelve halogenated thiourea (ATX 1-12) via chemical modification of aspirin (a natural product derivative) and evaluated for cytotoxic activity against nasopharyngeal carcinoma (NPC) cell lines, HK-1 via MTS-based colorimetric assay. The cytotoxicity studies demonstrated that halogens at meta position of ATX showed promising activity against HK-1 cells (IC₅₀ value ≤15?µM) in comparison to cisplatin, a positive cytotoxic drug (IC₅₀ value =8.9?±?1.9?µM). ATX 11, bearing iodine at meta position, showed robust cytotoxicity against HK-1 cells with an IC₅₀ value of 4.7?±?0.7?µM. Molecular docking interactions between ATX 11 and cyclooxygenase-2 demonstrated a robust binding affinity value of ?8.1?kcal/mol as compared to aspirin’s binding affinity value of ?6.4?kcal/mol. The findings represent a promising lead molecule from natural product with excellent cytotoxic activity against NPC cell lines.     

Potential of bifluorenylidene derivatives as nonfullerene small-molecule acceptor for heterojunction organic photovoltaics: a density functional theory study

To maximize the efficiency of heterojunction organic photovoltaics (HJOPVs), it is imperative to increase not only the open-circuit voltage (V _OC) but also the short-circuit current (I _SC). Therefore, it is desirable to find an organic acceptor material that possesses a higher lowest unoccupied molecular orbital (LUMO) level for higher V _OC and can absorb photons in the solar spectrum efficiently for larger I _SC. In this paper, in comparison with the typical donor poly(3-hexylthiophene) (P3HT) and acceptor [6,6]-phenyl-C₆₁-butyric acid ester ([60]PCBM), the geometries, electronic structures, absorption spectra, and transport properties of a series of organic compounds containing 9,9′-bifluorenylidene (9,9′BF) were systematically investigated using density functional and the semiclassical Marcus charge transfer theory calculation to evaluate their potential severing as acceptor. Our results indicate that the absorption spectra of 99′BF derivatives have better overlap with the solar spectrum than those of [60]PCBM, and higher LUMOs result in a significant enhancement of V _OC when they are used in HJOPVs with P3HT as donor materials. On the other hand, these compounds own higher electron carrier mobilities comparing with [60]PCBM. The study also demonstrates that the H-shaped compounds based on the 99′BF backbone possess good photophysical and charge transport properties, can be promising organic semiconductor for heterojunction photovoltaics.     

Green synthesis of diethyl((2-iodo-4-(trifluoromethyl)phenyl)amino)(aryl)methyl)phosphonates as potent α-glucosidase inhibitors

Abstract

Novel diethyl((2-iodo-4-(trifluoromethyl)phenyl)amino)(aryl)methyl)phosphonates (4a-j) were synthesized via a simple and efficient one pot by three-component condensation reaction (Kabachnik-Fields reaction) of 2-iodo-4-trifluoromethyl aniline, aromatic aldehydes and diethyl phosphite in presence of anatase TiO₂ nanoparticles as catalyst under solvent free conditions. The molecular docking studies of synthesized compounds with α-glucosidase enzyme revealed that these compounds have strong α-glucosidase inhibitory activity. The synthesized compounds (4a-j) are also screened for in vitro α-glucosidase inhibitory activity and the results showed compound 4i as the strongest inhibitor and compounds 4a, 4b, 4f and 4g as stronger inhibitors even better than the reference standard acarbose.     

Synthesis,Biological Evaluation,and Molecular Docking Studies of Novel Pyrazolo[3,4‐d]pyrimidines as Potential Telomerase Inhibitors

Series of novel pyrazolo[3,4‐d]pyrimidines as potential telomerase inhibitors were synthesized. Results of the antitumor assay indicated that compounds 4b , 5a – b , 13b , c , and 14a , b exhibited the most potent activity (IC₅₀ from 39 to 43 μM) against Ehrlich ascites carcinoma cells (EAC). Also, the newly synthesized compounds were examined for telomerase inhibition by the known a TRAP assay. The results showed that compound 13c has remarkable inhibition activity with IC₅₀ value of 30 μM. On the other hand, computational studies were performed to the titled compounds to get insight in their degree of recognition with the conserved amino acids of the telomerase enzyme active site (code: 3DU6) as promising lead in the cancer cure era.     

Synthesis,characterization and biological evaluation of some novel sulfonylthiosemicarbazides

Abstract

A series of thiosemicarbazides were synthesized and structurally characterized by spectroscopic techniques (NMR, FT-IR) besides elemental analysis. These compounds were evaluated for their cytotoxicity against human breast cancer cell line MCF7 and prostate cancer cell line PC3 and nonmalignant fibroblast L929 cell line by MTT assay. Among the compounds, N-[2-(4-chlorophenyl)ethyl]-2-[(4-methylphenyl)sulfonyl]hydrazinecarbothioamide (3d) and 2-[(4-methylphenyl)sulfonyl]-N-[4-(trifluoromethoxy)phenyl]hydrazinecarbothioamide (3f) were found to display significant cytotoxicity with IC₅₀ of 13.87?μM (against PC3 cell line) and 1.47?μM (against MCF7 cell line), respectively. These compounds were non-cytotoxic to normal cell line with IC₅₀>100?μM. Western blotting studies demonstrated that compound 3f induced apoptosis and caused cell death in the MCF7 and PC3 cell lines via an increase in Bax protein expression and a slight decrease in Bcl-2 protein expression. The gene expression ratio Bax/Bcl-2 showed the induction of mitochondrial apoptosis in cancer cell lines. All of synthesized compounds have also been tested for antioxidant activity and all compounds achieved strong inhibition of the DPPH radical. These findings showed that compound 3f, displays potential to be further explored in the development of new anticancer agents.     

Synthesis,crystal structure,spectral and electrochemical characterization,DNA binding and free radical scavenging studies of ferrocene-based thioureas

Abstract

Thioureas are important building blocks in medicinal chemistry; ferrocenes as highly hydrophobic moieties induce very interesting qualities in medicinal compounds. In this article, we have synthesized four ferrocene incorporated N,N′-disubstituted benzoyl thioureas (3a–3d) with general formula C₅H₅-Fe-C₅H₄C₆H₄Cl-NH-CS-NH-CO-C₆H₄(H/CH₃). Molecular structures of these compounds were characterized in solid and solution phases. In solution molecular structures were established by ¹H and ¹³C NMR and cyclic voltammetry. In the solid state their structures were characterized by elemental analyses and FTIR spectroscopy. Two of the compounds (3a and 3d) had also been structurally determined by single crystal X-ray diffraction analysis. The electrochemical characterization showed a reversible process with one electron transfer from Fe(II) to Fe(III). The single crystal analysis showed strong intermolecular non-covalent interactions in these compounds. Molecular structures of these compounds were also studied by density functional theory (DFT) calculation . DFT studies showed good correlation between calculated parameters and experimental results of solution phase and solid state characterizations. Compounds 3a–3d were evaluated for DNA interaction and antioxidant activity. These compounds interact with DNA via electrostatic forces and liberate significant binding constants and energies. Antioxidant potential –CSNH and –CONH groups induce same level of free radical scavenging ability in these compounds.     

Artificial neural network‐based drug design for diabetes mellitus using flavonoids

Diabetes mellitus is a chronic metabolic disease involving the failure to regulate glucose blood levels in the body and has been linked with numerous detrimental complications. Studies have shown that these complications can be linked to the activities of aldose reductase (AR), an enzyme of the polyol pathway. Flavonoids have been identified as good AR inhibitors (ARIs) and are also strong antioxidants with radical scavenging (RS) activity. As such, flavonoids show potential to become a better class of ARIs because they are able to concurrently address the oxidative stress issue. In this article, we carried out quantitative structure‐activity relationship analysis of flavones and flavonols (members of flavonoid family) using artificial neural networks. Three computer experiments were conducted to study the influence of hydrogen (H), hydroxyl (? OH), and methoxyl (? CH₃) functional groups on eight substitution sites of the lead flavone molecule and to predict potential ARIs. Of 6561 possible flavones and flavonols, in experiment 1, we predicted 69 potent ARIs, and in experiment 2, we predicted 346 compounds with strong RS activity. In experiment 3, we combined these results to find overlapping compounds with both strong AR inhibition and RS activity and we are able to predict 10 potent compounds with strong AR inhibition (IC₅₀ < 0.3 μM) and RS activity (IC₂₅ < 1.0 μM). These 10 compounds show promise of being good therapeutic agents in the prevention of diabetic complications and is suggested to undergo further wet bench experimentation to prove their potency. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Inhibiting the growth of tumor cells by ruthenium(II) complexes [Ru(phen)2L] (L = o-TFMPIP and p-CPIP) through DNA-binding

[Ru(phen)₂o-TFPIP]²⁺ (1) and [Ru(phen)₂p-CPIP]²⁺ (2) have been synthesized and demonstrated to inhibit the growth of tumor cells. The inhibitory activities (IC₅₀) of 1 against the growth of C6, MDA-MB-231 and HepG2 cells were about 24.5, 36.7, and 36.1 μM, respectively. Studies show that both complexes bind to CT-DNA, explained by using density functional theory calculations. The LogP calculated for 1 and 2 are ?0.4859 and ?1.279, respectively. These complexes, especially 1, can be used as promising inhibitors in chemotherapy, and their DNA-binding behaviors play a key role.     

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

Abstract

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13?g (IC₅₀ = 0.514?μM) and 13o (IC₅₀ = 0.275?μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC₅₀ = 0.511?μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.     

Docking-based 3D-QSAR study of pyridyl aminothiazole derivatives as checkpoint kinase 1 inhibitors

Checkpoint kinase 1 (Chk1) is a promising target for the design of novel anticancer agents. In the present work, molecular docking simulations and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed on pyridyl aminothiazole derivatives as Chk1 inhibitors. AutoDock was used to determine the probable binding conformations of all the compounds inside the active site of Chk1. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed based on the docking conformations and alignments. The CoMFA model produced statistically significant results with a cross-validated correlation coefficient (q²) of 0.608 and a coefficient of determination (r²) of 0.972. The reliable CoMSIA model with q² of 0.662 and r² of 0.970 was obtained from the combination of steric, electrostatic and hydrogen bond acceptor fields. The predictive power of the models were assessed using an external test set of 14 compounds and showed reasonable external predictabilities (r²_pred) of 0.668 and 0.641 for CoMFA and CoMSIA models, respectively. The models were further evaluated by leave-ten-out cross-validation, bootstrapping and progressive scrambling analyses. The study provides valuable information about the key structural elements that are required in the rational design of potential drug candidates of this class of Chk1 inhibitors.     

含二齿膦配体的二羰基铁化合物的制备及光诱导释放一氧化碳性能

一氧化碳释放剂(CORM)为CO在人体的精准输送提供了便利。为提高CORM的稳定性,以[Fe(CO)₄I₂]为前驱体,通过与二齿膦配体dppe、dppp、PNP(dppe=1,2-双(二苯基膦酰)乙烷,dppp=1,3-双(二苯基膦酰)丙烷,PNP=N-环己基-N-(二苯基膦酰)-1,1-二苯基膦胺(Ph₂PN(cyclohexyl)PPh₂)的配位取代反应制得了二齿膦二羰基铁化合物1~3,并利用FT-IR、UV-Vis、NMR、元素分析、单晶X射线衍射(化合物2、3)进行表征。通过红外光谱法研究了化合物1~3的降解释放CO性能,以评估其作为CORM的潜能。在二甲亚砜溶剂中、黑暗条件下这些化合物表现出良好稳定性;但在可见光(红光、绿光、蓝光)照射下,均可降解释放CO,其降解速率与光源的能量和化合物的结构有关。此外,在蓝光和绿光照射下,发现化合物1和2可从顺式构型向反式构型发生转化,而红光下因能量不足未见构型转化。     

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.     

Anti-inflammatory activity of saponins from roots of Impatiens parviflora DC.

Abstract

Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti-hyaluronidase effect of IPS-2 (IC₅₀?=?286.7?µg/mL) was higher than that of the reference drug: escin (IC₅₀?=?303.93?µg/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC₅₀?=?86.7?µg/ml) than IPS-2 (IC₅₀?=?109.76?µg/mL) or the standard drug: acetylsalicylic acid (IC₅₀?=?262.22?µg/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid.     

Hydroxamic Acids as PARP-1 Inhibitors: Molecular Design and Anticancer Activity of Novel Phenanthridinones

Poly(ADP-ribose)polymerase-1 (PARP-1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N−O substituted phenanthridinones form a complex interplay with PARP-1. A series of cyclic aryl hydroxamic acids, N-(benzyloxy)- and N-(hydroxy)phenanthridinones, were prepared through a ligand-free methodology from N-(benzyloxy)benzamides using dual C−H/N−H bond activation. Three of the computed hit compounds exhibited significant activity in cell-based and enzymatic assays, inhibiting PARP-1 in the low-nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA-MD-231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N-(benzyloxy)- and an N-(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target-specific design to minimize toxicity and side effects.     

Synthesis and monoamine oxidase A/B inhibitory evaluation of new benzothiazole-thiazolylhydrazine derivatives

Abstract

In this study, a novel series of benzothiazole-thiazolylhydrazine (3a–3i) was synthesized and their structures were characterized by ¹H-NMR, ¹³C-NMR spectrometry, and mass spectroscopy. These compounds were evaluated as inhibitors of type A and type B monoamine oxidase (MAO) enzymes. The most active compound 3b (2-((2-(2-(4-(4-Nitrophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed strong inhibitory activity at hMAO-A (IC₅₀ of 0.095?±?0.004?µM). Furthermore, compound 3i (2-((2-(2-(4-(2,4-dichlorophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed significant inhibition profile on hMAO-A with the IC₅₀ values 0.141?±?0.006?µM.