Synthesis of 4-amino-4,5-dideoxy-L-lyxofuranose derivatives and their evaluation as fucosidase inhibitors

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM).     

Synthesis and cytotoxic activities of 4,5-diarylisoxazoles

A series of 4,5-diarylisoxazoles related to combretastatin A-4 (CA-4) were synthesized and evaluated for cytotoxicity against three human cancer cell lines. Among them, compound 6e showed better cytotoxic activity than CA-4 in HeLa and HepG2 cell lines assayed with IC(50) value as low as 0.022 and 0.065nM, respectively.     

Synthesis of 2-methoxybenzoylhydrazone and evaluation of their antileishmanial activity

Compounds 1–25 showed varying degree of antileishmanial activities with IC₅₀ values ranging between 1.95 and 88.56 μM. Compounds 2, 10, and 11 (IC₅₀ = 3.29 ± 0.07 μM, 1.95 ± 0.04 μM, and 2.49 ± 0.03 μM, respectively) were found to be more active than standard pentamidine (IC₅₀ = 5.09 ± 0.04 μM). Compounds 7 (IC₅₀ = 7.64 ± 0.1 μM), 8 (IC₅₀ = 13.17 ± 0.46 μM), 18 (IC₅₀ = 13.15 ± 0.02 μM), and 24 (IC₅₀ = 15.65 ± 0.41 μM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20–25 showed weak activities with IC₅₀ values ranging between 57 and 88 μM.     

Abietane diterpenoids and triterpenoic acids from Salvia cilicica and their antileishmanial activities

Bioguided-fractionation of an acetone extract of the roots of Salvia cilicica (Lamiaceae) led to isolation of two new diterpenes, 7-hydroxy-12-methoxy-20-nor-abieta-1,5(10),7,9,12-pentaen-6,14-dione and abieta-8,12-dien-11,14-dione (12-deoxy-royleanone), together with oleanolic acid, ursolic acid, ferruginol, inuroyoleanol and cryptanol. Their structures were determined spectroscopically, which included HREIMS and 2D NMR spectroscopic analysis. The new abietane derivatives showed appreciable in vitro antileishmanial activity against intracellular amastigote forms of both Leishmania donovani (IC(50) values of 170 and 120 nM, respectively) and Leishmania major (IC(50) values of 290 and 180 nM, respectively). The triterpenoic acids were found to be potently active against amastigote (IC(50) values of 7-120 nM) and moderately active against promastigote stages (IC(50) values of 51-137 nM) of the two Leishmania species.     

Synthesis and evaluation of original amidoximes as antileishmanial agents

An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald–Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 μM IC₅₀ values. Moreover, the cytotoxicity of these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited a better selectivity index than pentamidine used as a drug compound reference.     

Synthesis of chromenochalcones and evaluation of their in vitro antileishmanial activity

A large number of novel chromenochalcones were synthesized by pyridine-catalysed chromenylation of mono-chelated meta-dihydric acetophenones with the monoterpene, citral dimethyl acetal and subsequent Claisen-Schmidt condensation of the resultant acylchromenes with appropriate aromatic aldehydes. These chromenochalcones 1-19 were screened against in vitro extracellular promastigotes and intracellular amastigotes of Leishmania donovani. The most potent compound in this series was compound 9 with a pyridine ring-A, which showed 99% inhibition of promastigotes at 10 microg/ml, 82% at 0.25 microg/ml and 96% at 10 microg/ml concentration against amastigotes.     

Synthesis and antileishmanial evaluation of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazole derivatives

A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a–g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a–g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC₅₀ values ranging from 15 to 60 μM. The reference drug pentamidine presented IC₅₀ = 10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.     

Synthesis of novel 4'-C-methyl-pyrimidine nucleosides and their biological activities

Two novel 4'-C-methylnucleosides, 4'-methylBVDU 9 and 4'-methylBVaraU 10, were synthesized. The former was derived from 3',5'-di-O-acetyl-2'-deoxy-4'-C-methyluridine 12, and the latter was produced via glycosylation between 4-C-methyl-D-ribose derivative 11 and a silylated bromovinyl uracil. 4'-MethylBVDU 9 exhibited particularly potent anti-varicella-zoster virus (VZV) activity in vitro.     

Synthesis and biological evaluation of trifluralin analogues as antileishmanial agents

A series of new analogues of trifluralin (TFL) were synthesized and characterized in view of changing the unfavorable properties that limits its use as antileishmanial agent. Some of the TFL analogues display more activity than a standard drug (miltefosine) against the promastigote forms of Leishmania infantum and Leishmania donovani and the intracellular form (THP-1 infected with L. infantum). All analogues showed a clear advantage over miltefosine, as they are not hemolytic. Some analogues can conjugate these characteristics with reduced cell toxicity and improved intracellular activity.     

Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities

A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.     

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.     

Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones as antileishmanial and antifungal agents

A series of highly functionalized thiophene (2) and thieno[3,2-c]pyran-4-one(4) derivatives have been synthesized and evaluated for their antileishmanial and antifungal activities.     

Synthesis and structure-activity relationships of 9-substituted acridines as endothelin-A receptor antagonists

Screening of a compound library against endothelin receptors (ET_A and ET_B) revealed PD 102566 (compound 1) as an ET_A selective antagonist. Synthesis and structure-activity relationships (SAR) of a series of analogs are described.     

Synthesis of furanosyl alpha-C-glycosides derived from 4-chloro-4-deoxy-alpha-D-galactose and their cytotoxic activities

Condensation of a new unnatural sugar 1 with 1,3-dicarbonyl compounds in the presence of anhydrous zinc chloride gave the polyhydroxyalkyl-furans in excellent yields. Further modification afforded the corresponding furanosyl alpha-C-glycoside derivatives. The absolute configuration of 3-acetyl-2-methyl-5-(2'-chloro-D-galacto-tetritol-1-yl)-furan was confirmed by single-crystal X-ray analysis. The in vitro cytotoxic activities of these furanosyl C-glycosides were also investigated.     

Synthesis of 2,4,6-trisubstituted pyrimidine and triazine heterocycles as antileishmanial agents

A series of 2,4,6 trisubstituted pyrimidines and triazines have been synthesized and screened for its in vitro antileishmanial activity profile in promastigote model. Nine compounds have shown > 94% inhibition against promastigotes at a concentration of 10 microg/mL.     

Synthesis, antimalarial, antileishmanial, and antimicrobial activities of some 8-quinolinamine analogues

In the present communication, newly synthesized 8-quinolinamines (25-27) related to previously reported 2-tert-butylprimaquine (2) were evaluated for their in vitro antimalarial activity against chloroquine sensitive and resistant Plasmodium falciparum strains, in vivo antimalarial activity against P. berghei infected mice, in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity against various fungi and bacteria, and cytotoxicity in a panel of mammalian cell lines. No promising cytotoxicities were observed for compounds reported herein. Analogue 25 was found to exhibit curative antimalarial activity at a dose of 25 mg/kg/dayx4 in a P. berghei infected mice model, and produced suppressive activity at a lower dose of 10 mg/kg/dayx4. In vitro antileishmanial activities (IC50 and IC90) comparable to standard drug pentamidine were exhibited by all synthesized 8-quinolinamines 25-27. At the same time, promising antibacterial and antifungal activities were also observed for synthesized compounds against a panel consisting of several bacteria and fungi.     

Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent

The devastating appearance of numerous drug-unresponsive strains of Leishmania donovani and severe toxic side effects of conventional antileishmanial therapy necessitates the search for novel leads, to treat visceral leishmaniasis efficiently. The current study deals with the synthesis and biological evaluation of a unique C-5 functionalized oxindole based polyphenol to ascertain its activities against L. donovani infection, in vitro. The polyhydroxylated oxindole derivative (1) was generated by coupling styrene derivatives with 5-bromo bis-arylidene oxindole using Heck coupling reaction. The synthesized molecule 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Molecule 1 showed promising anti-promastigote and anti-amastigote activities with IC₅₀ values 15?µM and 1?µM, respectively, with no cytotoxicity towards host splenocytes. The results revealed that this compound induced parasite death by promoting oxidative stress, thereby triggering apoptosis.     

Synthesis of C-1 homologues of pancratistatin and their preliminary biological evaluation

The synthesis of two C-1 analogues of pancratistatin has been accomplished in 17 steps from bromobenzene. The key steps involved the enzymatic dihydroxylation, regioselective opening of epoxyaziridine 9 with the alane derived from 8, a solid-state silica-gel-catalyzed intramolecular opening of aziridine to produce phenanthrene 13 whose oxidative cleavage and recyclization provided the full skeleton of the Amaryllidaceae constituents. The new analogues 5 and 6 exhibited promising activity in several human cancer cell lines.     

Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents

As a part of our project aimed at developing new safe chemotherapeutic agents against tropical diseases, a series of aryl derivatives of 2- and 3-aminoquinoline, some of them new compounds, was designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas’ disease), and Leishmania mexicana, the etiological agent of Leishmaniasis. Some of them showed a remarkable activity as parasite growth inhibitors. Fluorine-containing derivatives 11b and 11c were more than twice more potent than geneticin against intracellular promastigote form of Leishmania mexicana exhibiting both IC₅₀ values of 41.9 μM. The IC₅₀ values corresponding to fluorine and chlorine derivatives 11b–d were in the same order than benznidazole against epimastigote form. These drugs are interesting examples of effective antiparasitic agents with outstanding potential not only as lead drugs but also to be used for further in vivo studies. In addition, the obtained compounds showed no toxicity in Vero cells, which makes them good candidates to control tropical diseases. Regarding the probable mode of action, assayed quinoline derivatives interacted with hemin, inhibiting its degradation and generating oxidative stress that is not counteracted by the antioxidant defense system of the parasite.     

Synthesis of 4-amino-4,5-dideoxy-l-lyxofuranose derivatives and their evaluation as fucosidase inhibitors

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-l-lyxofuranose) was synthesised from d-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-l-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-l-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-l-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K_i = 8 vs 10 nM).