Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N⁶ alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N⁶ positions reduced activity against both enzymes.     

New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis,in vitro evaluation and in silico study

A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063–0.5 µg/mL had the best profile of activity, being 4–32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.     

Synthesis of benzologues of Nitazoxanide and Tizoxanide: a comparative study of their in vitro broad-spectrum antiprotozoal activity

We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC₅₀’s <5μM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent.     

A novel achiral seco-cyclopropylpyrido[e]indolone (CPyI) analog of CC-1065 and the duocarmycins: Synthesis,DNA interactions,in vivo anticancer and anti-parasitic evaluation

The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.     

One pot three components microwave assisted and conventional synthesis of new 3-(4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one as antimicrobial agents

A one-pot, three-component, microwave assisted and conventional synthesis of new 3-(4-chloro-2-hydroxyphenyl)-2-(substituted) thiazolidin-4-one (4a–n) was carried out by using N,N-dimethylformamide as a solvent with high product yield. Among these synthesized compounds (4f, 4g, 4l and 4m) were found to be a broad spectrum molecule active against all bacterial and fungus strains tested, except fungus Aspergillus niger. Amongst the compounds (4g, 4l and 4m) were found to be more potent than respective standard drugs used in the experiment against Candida albicans, Staphylococcus aureus and Aspergillus flavus, respectively. All synthesized compounds were also tested for their cytotoxic activity against HeLa and MCF-7 cell lines by the sulforhodamine B (SRB) assay. This study shows that all compounds were non-cytotoxic in nature, and confirmed their antimicrobial specificity apart from any general cytotoxicity.     

Lignans from the fruit of Schisandra sphenanthera,and their inhibition of HSV-2 and adenovirus

The systematic isolation of the EtOAc extract from Schisandra sphenanthera fruit was performed during a search for HSV-2 and adenovirus inhibitors. Sixteen lignans were obtained, with compound 1 representing a new and rare type of lignan in the genus Schisandra. Their structures were elucidated by spectroscopy and comparison with literature data. Among all the lignans tested for their antiviral activities, compound 14 was the most active against HSV-2 with a selectivity index value up to 29.83. Moreover, the new compound 1, and the known ones (4, 6, 7, 10 and 14) also exhibited moderate inhibition of HSV-2 and adenovirus. To the best of our knowledge, this is the first report that these lignans from Schisandra genus were shown to have modest activity against HSV-2 and adenovirus. Meanwhile, structure–activity relationships of some lignans for the inhibitory activity against HSV-2 and adenovirus were discussed in this study.     

Synthesis of novel 1,2-bis-quinolinyl-1,4-naphthoquinones: ERK2 inhibition,cytotoxicity and molecular docking studies

Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones 1a-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL Et₃N. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e,f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATP-competitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor sub-panels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI₅₀ and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.     

Ultrasonication-ionic liquid synergy for the synthesis of new potent anti-tuberculosis 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines

The aim of the study is to design and synthesis of a new series of potent anti-TB 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines with their safety profile. A synergetic effect of ultrasonication and ionic liquid was shown successfully as a green methodology for the synthesis of title compounds 6a–t. These derivatives were obtained in shorter reaction time with good yields and well characterized by various spectroscopic methods, single-crystal X-ray diffraction (6f). The in vitro anti-tuberculosis activity for newly-synthesized derivatives has been screened against Mycobacterium tuberculosis. Among all, six compounds 6e, 6k, 6l, 6n, 6q and 6r exhibited equal potent activity compared to standard drug ethambutol (MIC: 1.56 µg/mL) and another compound 6h exhibited outstanding activity (MIC: 0.78 µg/mL) than the standard drug ethambutol. Cytotoxic nature of the anti-TB active compounds was evaluated against RAW 264.7 cells. The 6h, 6e, 6k, 6l, 6n, 6q and 6r exhibited lower toxicity which could be promising hits for anti-tuberculosis.     

Discovery of novel arylpyrazole series as potent and selective opioid receptor-like 1 (ORL1) antagonists

The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure–activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.     

Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies

A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC₅₀ of 0.25 μM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.     

Synthesis and anti-proliferative activity of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs against human tumor cell lines

Based on previous SAR studies on N-benzylindole and barbituric acid hybrid molecules, we have synthesized a series of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs (3a–i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds 3c, 3d, 3f and 3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI₅₀ values in low the nanomolar range. The 4-methoxy-N-benzyl analog (3d) was the most active compound with GI₅₀ values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, 3c (the 4-methyl-N-benzyl analog) and 3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI₅₀ = 30 nM). Analog 3f (the 4-chloro-N-benzyl analog) exhibited a GI₅₀ value of 40 nM against renal cancer cell line A498. These results suggest that aromatic substituted N-benzylindole dimethylbarbituric acid hybrids may have potential for development as clinical candidates to treat a variety of solid tumors.     

Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes

Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η⁶-benzyldimethylamine)tricarbonylchromium 2, [η⁶-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η⁶-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC₅₀ values of 33.9 nM versus 63.1 nM).     

Synthesis and antimycobacterial activity of highly functionalized tetrahydro-4(1H)-pyridinones

A series of 35 2e,3e,6e-triaryltetrahydro-4(1H)-pyridinones, 2e,3e,5e,6e-tetraaryltetrahydro-4(1H)-pyridinones and their N-nitroso and N-cyano analogs have been prepared. All these 35 compounds obtained were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB). Among them, the N-nitrosopyridinones are found to be more active against MTB than the corresponding N-CN analogs, which, in turn, were slightly more active than NH analogs. In particular, the N-nitroso compounds, 3d, 4b and 4e with halogen-bearing phenyl rings at 2,6-positions showed maximum activity with MIC values of 3.97, 3.11 and 3.11 μM, being more efficacious than the first line anti-TB drugs, ciprofloxacin, ethambutol and pyrazinamide. A general trend has also been discerned in all the three classes of NH, N-CN and N-NO compounds, in each of which those bearing four aryl rings display higher activity than that having three analogously substituted aryl rings disclosing that lipophilicity could be an important factor underlying antimycobacterial activity.     

Synthesis,characterization and in vitro biological evaluation of some novel 1,3,5-triazine–Schiff base conjugates as potential antimycobacterial agents

A series of some novel 1,3,5-triazine–Schiff base conjugates (1–32) have been synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using Alamar Blue assay and the activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Compounds 4 (4-Methoxy-6-methyl-N-(3,4,5-trimethoxybenzylidene)-1,3,5-triazin-2-amine), 11 (4-Methoxy-6-methyl-N-(2-hydroxy-3-bromo-5-chloro-benzylidene)-1,3,5-triazin-2-amine) and 24 (4-Methoxy-6-methyl-N-(1-(2,5-dihydroxyphenyl)ethylidene)-1,3,5-triazin-2-amine) exhibited a significant activity at 3.125, 6.25 and 6.25 μg/mL, respectively, when compared with the antitubercular drugs such as ethambutol (3.125 μg/mL), pyrazinamide (6.25 μg/mL) and streptomycin (6.25 μg/mL) and it could be a potential starting point to develop new lead compounds in the fight against Mycobacterium tuberculosis H37Rv.     

Polyhydroxylated azetidine iminosugars: Synthesis,glycosidase inhibitory activity and molecular docking studies

An efficient and practical strategy for the synthesis of unknown azetidine iminosugars (2S,3R,4S)-2-((R)-1,2-dihydroxyethyl)-3-hydroxy-4-(hydroxymethyl)azetidine 2, (2S,3r,4R)-3-hydroxy-2,4-bis(hydroxymethyl)azetidine 3 and (2S,3R,4S)-3-hydroxy-4-(hydroxymethyl)-N-methylazetidine-2-carboxylic acid 4, starting from the d-glucose has been reported. The methodology involves preparation of the 3-amino-N-benzyloxycarbonyl-3-deoxy-6-O-tert-butyldimethylsillyl-1,2-O-isopropylidene-α-d-glucofuranose 9, which was converted to the C-5-OMs derivative 11. Intramolecular nucleophilic displacement of the C-5-OMs group with in situ generated 3-amino functionality provided the required key azetidine ring skeletons 10 with additional hydroxymethyl group. Removal of 1,2-acetonide protection, followed by reduction and hydrogenolysis afforded azetidine iminosugar 2. Alternatively, removal of 1,2-acetonide group and chopping of C1-anomeric carbon gave C2-aldehyde that on reduction or oxidation followed by hydrogenolysis gave 2,4-bis(hydroxymethyl) azetidine iminosugars 3 and N-methylazetidine-2-carboxylic acid 4 respectively. The glycosidase inhibitory activity of 2–4 iminosugars was screened against various glycosidase enzymes and compared with a standard miglitol. Amongst synthesized targets, the compound 2 was found to be more potent amyloglucosidase inhibitor than miglitol. These results were supported by molecular docking studies.     

Design,synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors—Part 2

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood–brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H³)methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.     

Trinorsesquiterpenoids from Inula racemosa

Four trinorsesquiterpenoids (1–4) were isolated from the roots of Inula racemosa and the structures of two new compounds, (4R,5S,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (1) and (4R,5R,10R)-4,15-epoxy-11,12,13-trinoreudesman-8-one (3), were elucidated by extensive spectroscopic analysis. Furthermore, the structure of compound 2a should be revised as (4R,5R,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (2) and compound 2 showed antiproliferative activity against A549, HepG2, and HT1080 cell lines with IC50 values of 3.71, 5.94, and 3.95 μg/mL, respectively.     

Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines

Novel riminophenazine derivatives, characterized by the presence of the basic and cumbersome quinolizidinylalkyl and pyrrolizidinylethyl moieties, have been synthesized and tested (Rema test) against Mycobacterium tuberculosis H₃₇R_v and H₃₇R_a, and six clinical isolates of Mycobacterium avium and Mycobacterium tuberculosis. Most compounds exhibited potent activity against the tested strains, resulting more active than clofazimine, isoniazid and ethambutol.The best compounds (4, 5, 12 and 13) exhibited a MIC in the range 0.82–0.86 μM against all strains of Mycobacterium tuberculosis and, with the exception of 4 a MIC around 3.3 μM versus M. avium. The corresponding values for clofazimine (CFM) were 1.06 and 4.23 μM, respectively. Cytotoxicity was evaluated against three cell lines and compound 4 displayed a selectivity index (SI) versus the human cell line MT-4 comparable with that of CFM (SI = 5.23 vs 6.4). Toxicity against mammalian Vero 76 cell line was quite lower with SI = 79.     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

Synthesis of 1H-1,2,3-triazole derivatives as new α-glucosidase inhibitors and their molecular docking studies

Inhibition of α-glucosidase is an effective strategy for controlling the post-prandial hyperglycemia in diabetic patients. For the identification of new inhibitors of this enzyme, a series of new (R)-1-(2-(4-bromo-2-methoxyphenoxy) propyl)-4-(4-(trifluoromethyl) phenyl)-1H-1,2,3-triazole derivatives were synthesized (8a–d and 10a–e). The structures were confirmed by NMR, mass spectrometry and, in case of compound 8a, by single crystal X-ray crystallography. The α-glucosidase inhibitory activities were investigated in vitro. Most derivatives exhibited significant inhibitory activity against α-glucosidase enzyme. Their structure-activity relationship and molecular docking studies were performed to elucidate the active pharmacophore against this enzyme. Compound 10b was the most active analogue with IC₅₀ value of 14.2 µM, while compound 6 was found to be the least active having 218.1 µM. A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in 1H-1,2,3-triazole derivatives is responsible for this activity and can be used as anti-diabetic drugs. The molecular docking studies of all active compounds were performed, in order to understand the mode of binding interaction and the energy of this class of compounds.