Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC₅₀ values of ?10 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC₅₀ of 0.37 μM and the highest tumor specificity.     

Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense and Plasmodium falciparum

A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC₅₀ values less than 7 nM against T. b. r. Twelve of those exhibited IC₅₀ values less than 6 nM against P. f. and six of those showed IC₅₀ values 0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.     

Exploration of SAR regarding glucose moiety in novel C-aryl glucoside inhibitors of SGLT2

In order to investigate SAR regarding glucose moiety in novel C-aryl glucoside SGLT2 inhibitors containing a thiazole motif, a series of chemical modifications on glucose was conducted to explore potential utility as a suitable replacement of glucose per se. Among the compounds prepared, deshydroxy 29 (IC₅₀ = 7.01 nM) demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date. But, none of the compounds were better than the parent molecule 5 (IC₅₀ = 1.75 nM).     

Selective leishmanicidal effect of 1,3,4-thiadiazole derivatives and possible mechanism of action against Leishmania species

With the aim of determining selectivity and the possible target(s) of nitroheteroaryl-1,3,4-thiadiazoles considered as possible leads for the development of anti-leishmanial agents, we studied 5-nitroimidazole, 5-nitrofuran and 5-nitrothiophene analogs of N-substituted-piperazinyl-1,3,4-thiadiazoles. We investigated 21 representative compounds 1-3(a-g) for the following properties: selectivity and efficiency against different Leishmania wild type species and intracellular parasite, toxicity against host cells and inhibition of topoisomerases I and II. Our results indicate that the nitroimidazole analogs 1a and 1f, and nitrofuran derivatives 2a, 2b, 2c, 2f, and 2g exhibited low toxicity against the host cells (IC₅₀ ? 80 μM), but high selectivity against intracellular amastigotes (selectivity index > 12). Leishmania topoisomerases revealed impressive sensitivity to the agents (%inhibition >50 at IC₅₀ doses of compounds against Leishmania). Our findings showed that at least part of leishmaniacidal effect of the compounds could be attributed to disruption DNA-relaxed activities of topoisomerases I and II, and cleavable-complex formation.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents

A series of boron-containing benzoxaborole compounds was designed and synthesized for a structure-activity relationship investigation surrounding 7-(HOOCCH₂CH₂)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1) with the goal of discovering a new antimalarial treatment. Compound 1 demonstrates the best potency (IC₅₀ = 26 nM) against Plasmodium falciparum and has good drug-like properties, with low molecular weight (206.00), low ClogP (0.86) and high water solubility (750 μg/mL at pH 7).     

NF kappa B inhibitors and antitrypanosomal metabolites from endophytic fungus Penicillium sp. isolated from Limonium tubiflorum

Chemical investigation of the endophytic fungus Penicillium sp. isolated from Limonium tubiflorum growing in Egypt afforded four new compounds of polyketide origin, including two macrolides, penilactone (1) and 10,11-epoxycurvularin (2), a dianthrone, neobulgarone G (7), and a sulfinylcoumarin, sulfimarin (14), along with twelve known metabolites (3-6, 8-13, 15 and 16). The structures of all compounds were assigned by comprehensive spectral analysis (1D and 2D NMR) and mass spectrometry. Compounds 3, 4, 13 and 16 showed pronounced antitrypanosomal activity with mean MIC values ranging from 4.96 to 9.75 ??M. Moreover, when tested against a panel of three human tumor cell lines compounds 3, 4, 6 and 12 showed selective growth inhibition against Jurkat and U937 cell lines with IC₅₀ values ranging from 1.8 to 13.3 ??M. The latter compounds also inhibited TNF??-induced NF-??B activity in K562 cells with IC₅₀ values ranging from 1.6 to 10.1 ??M, respectively.     

Zinc(II) complexes of 2-acetyl pyridine 1-(4-fluorophenyl)-piperazinyl thiosemicarbazone: Synthesis, spectroscopic study and crystal structures - Potential anticancer drugs

2-Acetyl pyridine thiosemicarbazone containing an 1-(4-fluorophenyl)-piperazinyl ring incorporated at N(4)-position, HAcPipPheF (1) and the zinc(II) complexes [Zn(AcPipPheF)₂] (2) and [Zn(OAc)(AcPipPheF)]₂ (3) have been prepared and structurally characterized by means of vibrational and NMR (¹H and ¹³C) spectroscopy. The crystal structures of the compounds 1-3 have been determined by X-ray crystallography. The metal coordination geometry of [Zn(AcPipPheF)₂] is described as distorted octahedral configuration in a trans-N-cis-N-cis-S configuration. In [Zn(OAc)(AcPipPheF)]₂ one of the acetato group exhibits monoatomic bridge and the other bridges in a bidentate manner. The zinc(1) metal ion is coordinated in a distorted octahedral configuration while the metal coordination of Zn(2) is described as distorted square pyramidal. Biomedical studies revealed that, compounds 1-3 displayed potent anticancer activity. The antiproliferative activity of 1-3 was found to be considerably stronger than that of cis-platin. The IC₅₀ values range from 26 to 90 nM, against all cell lines tested, while for cis-platin the IC₅₀ values range from 2 to 17 μM and for the zinc salt, ZnCl₂, the IC₅₀ values range from 81 to 93 μM. The complex 3 shows the highest activity against all four cancer cell lines and the highest selectivity against K562 and MDA-MB-453 cancer cell lines. The compounds inhibited tumor cell proliferation by arresting the cell cycle progression at the S phase.     

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Isolation of substances with antiproliferative and apoptosis-inducing activities against leukemia cells from the leaves of Zanthoxylum ailanthoides Sieb. & Zucc

Extraction of the leaves of Zanthoxylum ailanthoides Sieb. & Zucc. affords extracts and four isolated compounds which exhibit activities against leukemia cells. The chloroform-soluble fraction (ZAC) of the crude extract of this plant showed cytotoxic activity against human promyelocytic leukemia (HL-60) and myelomonocytic leukemia (WEHI-3) cells with IC₅₀ values of 73.06 and 42.22 μg/mL, respectively. The active ZAC was further separated to yield pheophorbide-a methyl ester (1), pheophorbide-b methyl ester (2), 13²-hydroxyl (13²-S) pheophorbide-a methyl ester (3) and 13²-hydroxyl (13²-R) pheophorbide-b methyl ester (4) whose structures were confirmed by spectroscopic methods. Compounds 2-4 showed cytotoxic activities against both leukemia cells with IC₅₀ value in the range of 46.76-79.43 nM, whereas compound 1 exhibited only weak cytotoxic activity. The extracts and compounds 1-4 also induced apoptosis and DNA damage in leukemia cells after treatment. The results suggested that the Z. ailanthoides is biologically active against leukemia cells.     

Pregnane alkaloids from Pachysandra axillaris

Nine new pregnane alkaloids, pachysamines J-R (1-9), together with seven known ones, were isolated from Pachysandra axillaris. The chemical structures of the new alkaloids were elucidated by spectroscopic methods. All the compounds were evaluated for their inhibitory activities against HL-60, SMMC-7721, A-549, SK-BR-3, and PANC-1 cell lines. Compound 15 possessed moderate activities against A-549, SK-BR-3, and PANC-1 cells, with the IC₅₀ values of 11.17, 4.17, and 10.76 μM, respectively. Besides, compound 11 showed cytotoxicities against A-549 cell, with the IC₅₀ values as 24.94 μM.     

Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles

The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11-22 is described. Compounds 11-22 have been obtained by Friedländer-type reaction of 2-aminopyridine-3-carbonitriles 1-10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC₅₀ (EeAChE: 14 nM); IC₅₀ (eqBuChE: 5.2 ??M]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC₅₀ (EeAChE: 64 nM); IC₅₀ (eqBuChE: 9.6 ??M] showed that this compound is a mixed-type inhibitor (K_i = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11-22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K⁺-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11-22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases.     

Biotransformation of natural compounds. Oxido-reduction of Sch-642305 by Aspergillus ochraceus ATCC 1009

Sch-642305 is the major compound produced by the endophytic fungi Phomopsis sp. CMU-LMA. Incubation of Sch-642305 with Aspergillus ochraceus ATCC 1009 resting cells leads to three new derivatives through an oxido-reduction of the six-membered ring of the molecule. Reduction of the double bound leads to compound (1), which subsequently undergoes carbonyl reduction to (2) and ring hydroxylation to (3). According to the previously solved crystal structure of Sch-642305 coupled with ¹H NMR NOE correlation and the crystal structure of compound 1, the absolute configurations of the new derivatives were established. In contrast to the parent compound Sch-642305, compound (1) exhibits antimicrobial activity against Gram-negative bacteria. Furthermore, while all derivatives exhibit cytotoxic activity against various cancer cell lines, compound (2) achieved an IC₅₀ of 4 nM against human myelogenous leukemia K 562, compared to 20 nM for the parent Sch-642305.     

Withanolides from Withania aristata and their cytotoxic activity

Seven new withanolides (1-7), along with three known ones (8-10), were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 2D NMR experiments and spectrometric techniques, and the absolute configuration of 1 and 2 was established by CD analysis. In the search for new cytotoxic compounds from Withania species, the isolated compounds 1-9, along with two derivatives, were assayed for their cytotoxicity against HeLa, MCF-7 and A-549 human tumor cell lines. Derivative (4S,20R,22R)-27-acetoxy-4-p-bromobenzoyloxy-1-oxo-witha-2,5,16,24-tetraenolide (13) showed cytotoxicity against all the cell lines assayed with IC₅₀ values ranging from 2.8 to 3.6 μM, and (4S,20R,22R)-4,27-diacetoxy-4-hydroxy-1-oxo-witha-2,5,16,24-tetraenolide (12) exhibited an IC₅₀ value of 5.4 μM on the MCF-7 cell line.     

Gold(III) chloride catalyzed regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones and evaluation of anticancer potential towards human cervix adenocarcinoma

A highly regioselective synthesis of pyrano[3,4-b]indol-1(9H)-ones via gold(III) chloride catalyzed cycloisomerization of 3-ethynyl-indole-2-carboxylic acid was achieved in good to excellent yields. These compounds were screened for their in vitro cytotoxicity against human cervical (HeLa) cell lines. Out of ten compounds, three compounds (7d, 7e and 7j) showed comparable proliferation inhibitory activity against the standard drug cisplatin. Compound 7d was found to be the most efficacious with IC₅₀ value of 0.22 μM.     

Cytotoxic and antioxidant activities of diterpenes and sterols from the Vietnamese soft coral Lobophytum compactum

Two new diterpenes, lobocompactols A (1) and B (2), and five known compounds (3-7) were isolated from the methanol extract of the soft coral Lobophytum compactum using combined chromatographic methods and identified based on NMR and MS data. Each compound was evaluated for cytotoxic activity against A549 (lung) and HL-60 (acute promyelocytic leukemia) human cancer cell lines. Among them, compound 5 exhibited strong cytotoxic activity against the A549 cell line with an IC₅₀ of 4.97 ± 0.06 μM. Compounds 3, 4, and 7 showed moderate activity with IC₅₀ values of 23.03 ± 0.76, 31.13 ± 0.08, and 36.45 ± 0.01 μM, respectively. The cytotoxicity of 5 on the A549 cells was comparable to that of the positive control, mitoxantrone (MX). All compounds exhibited moderate cytotoxicity against the HL-60 cell line, with IC₅₀ values ranging from 17.80 ± 1.43 to 59.06 ± 2.31 μM. Their antioxidant activity was also measured using oxygen radical absorbance capacity method, compounds 1 and 2 exhibiting moderate peroxyl radical scavenging activity of 1.4 and 1.3 μM Trolox equivalents, respectively, at a concentration of 5 μM.     

Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani

World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC₅₀ ∼ 20.7 μM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC₅₀ ∼ 7.2 μM) as compared to diospyrin (IC₅₀ ∼ 12.6 μM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC₅₀ ∼ 0.18 μM). Also, treatment of infected BALB/c mice with D17 at 2 mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.     

Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents

A series of novel substituted (Z)-5-((1-benzyl-1H-indol-3-yl)methylene)imidazolidin-2,4-diones (3a-f) and (Z)-5-((1-benzyl-1H-indol-3-yl)methylene)-2-iminothiazolidin-4-ones (3g-o) have been synthesized utilizing microwave irradiation. These analogs were evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3i exhibits potent growth inhibition against melanoma UACC-257 (GI₅₀ = 13.3 nM) and OVCAR-8 ovarian (GI₅₀ = 19.5 nM) cancer cells while possessing significant cytotoxicity (LC₅₀ = 308 nM and LC₅₀ = 851 nM, respectively) against the same cell lines within this series of compounds. A second analog, 3a, had GI₅₀ values of 307 and 557 nM against SK-MEL-2 melanoma and A498 renal cancer cell lines, and exhibited GI₅₀ values ranging from 0.30 to 6 μM against 98% of all cancer cell lines in the 60-cell panel. Thus, (Z)-5-((5-chloro-1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)-2-iminothiazolidin-4-one (3i) and (Z)-methyl 1-(4-cyanobenzyl)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-1H-indole-6-carboxylate (3a) can be regarded as useful lead compounds for further structural optimization as antitumor agents.     

Evaluation of in vitro cytotoxicity and hepatotoxicity of platinum(II) and palladium(II) oxalato complexes with adenine derivatives as carrier ligands

In vitro antitumour activity of the [Pt(ox)(L_n)₂] (1-7) and [Pd(ox)(L_n)₂] (8-14) oxalato (ox) complexes involving N6-benzyl-9-isopropyladenine-based N-donor carrier ligands (L_n) against ovarian carcinoma (A2780), cisplatin resistant ovarian carcinoma (A2780cis), malignant melanoma (G-361), lung carcinoma (A549), cervix epitheloid carcinoma (HeLa), breast adenocarcinoma (MCF7) and osteosarcoma (HOS) human cancer cell lines was studied. Some of the tested complexes were even several times more cytotoxic as compared with cisplatin employed as a positive control. The improved cytotoxic effect was demonstrated for the platinum(II) complexes 3 (IC₅₀ = 3.2 ± 1.0 μM and 3.2 ± 0.6 μM) and 5 (IC₅₀ = 4.0 ± 1.0 μM and 4.1 ± 1.4 μM) against A2780 and A2780cis, as compared with 11.5 ± 1.6 μM, and 30.3 ± 6.1 μM determined for cisplatin, respectively. The significant in vitro cytotoxicity against MCF7 (IC₅₀ = 8.2 ± 3.8 μM for 12) and A2780 (IC₅₀ = 5.4 ± 1.2 μM for 14) was evaluated for the palladium(II) oxalato complexes, which again exceeded cisplatin, whose IC₅₀ equalled 19.6 ± 4.3 μM against the MCF7 cells. Selected complexes were also screened for their in vitro cytotoxic effect in primary cultures of human hepatocytes and they were found to be non-hepatotoxic.     

Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor

Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC₅₀ values ranging from 0.58 to 1.11 μM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity.