J.K. Saxena

Synthesis of novel thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials

In search of new 4-aminoquinolines which are not recognized by CQR mechanism, thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities. Thiourea derivative 3 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro model with an IC(50) of 6.07ng/mL and also showed an in vivo suppression of 99.27% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.

Protective effect of fruits of Morinda citrifolia L. on scopolamine induced memory impairment in mice: A behavioral, biochemical and cerebral blood flow study

ETHNOPHARMACOLOGICAL RELEVANCE Noni (Morinda citrifolia L.) is widely used for different illnesses including CNS disorders. Recently Noni has been reported to prevent amyloid beta induced memory impairment in mice. However, the influence of Noni on cholinergic system has not been explored so far. Therefore, present study was designed to investigate effect of Noni fruit on memory, cerebral blood flow (CBF), oxidative stress and acetylcholinesterase (AChE) activity in scopolamine induced amnesia model. MATERIALS AND METHODS Mice were orally treated with ethanolic extract of Noni fruit and chloroform, ethyl acetate and butanol fractions of ethanolic extract for three days. Scopolamine was administered 5 min prior to acquisition trial and memory function was evaluated by passive avoidance test. CBF was measured by laser doppler flowmetry. AChE activity and oxidative stress parameters were estimated in mice brain at the end of behavioral studies. Further, effect of ethanolic extract and its fractions (5-400 μg/ml) on AChE activity was measured in vitro. RESULTS Scopolamine caused memory impairment along with reduced CBF, increased AChE activity and oxidative stress in mice brain. Ethanolic extract of Noni fruits and its chloroform and ethyl acetate fractions significantly improved memory and CBF. However, butanol fraction had no effect. Further, increased oxidative stress and AChE activity following scopolamine was significantly attenuated by ethanolic extract of Noni and its fractions. Moreover ethanolic extract and its fractions showed dose dependent inhibition of AChE activity in vitro. CONCLUSION These observations suggest that Noni may be useful in memory impairment due to its effect on CBF, AChE and oxidative stress.

Synthesis of oxalamide and triazine derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activity

Frequency of malaria and its resistance to chemotherapeutic options are emerging rapidly. To counter this problem, a series of 4-aminoquinolines having oxalamide and triazine functionalities in the side chain were synthesized and screened for their antimalarial activities. Triazine derivative 48 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro assay with an IC(50) of 5.23 ng/mL and oxalamide derivative 13 showed an in vivo suppression of 70.45% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.

Antiplasmodial activity of novel keto-enamine chalcone-chloroquine based hybrid pharmacophores

A series of novel keto-enamine chalcone-chloroquine based hybrids were synthesized following new methodology developed in our laboratory. The synthesized compounds were screened against chloroquine sensitive strain (3D7) of Plasmodium falciparum in an in vitro model. Some of the compounds were showing comparable antimalarial activity at par with chloroquine. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii (chloroquine resistant N-67 strain), wherein compounds 25 and 27 each showed an in vivo suppression of 99.9% parasitaemia on day 4. Biochemical studies reveal that inhibition of hemozoin formation is the primary mechanism of action of these analogues.

Synthesis and bioevaluation of novel 4- aminoquinoline-tetrazole derivatives as potent antimalarial agents

A series of novel tetrazole derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities against both chloroquine-senstive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum as well as for cytotoxicity against VERO cell lines. Most of the synthesized compounds exhibited potent antimalarial activity as compared to chloroquine against K1-strain. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii following both intraperitoneal (ip) and oral administration, wherein compounds 20 and 23 each showed in vivo suppression of 99.99% parasitaemia on day 4.

Antidyslipidemic and antioxidative activities of 8-hydroxyquinoline derived novel keto-enamine Schiffs bases

8-Hydroxyquinoline when subjected to Duff reaction resulted in the formation of unexpected 7-methylaminomethylene-8-oxo-7, 8-dihydroquinoline-5-carbaldehyde 2, which existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted, which upon subsequent treatment with various primary amines resulted in its nucleophilic substitution of aliphatic methyl amine. These interesting novel derivatives were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic and post-heparin lipolytic activities. Compound 6 was found to be most active antidyslipidemic and antioxidative agent in this series, respectively, and thus represent a new class of promising lead.

Synthesis and in vitro evaluation of new chloroquine-chalcone hybrids against chloroquine-resistant strain of Plasmodium falciparum.

The control of malaria has been complicated with increasing resistance of malarial parasite against existing antimalarials. Herein, we report the synthesis of a new series of chloroquine-chalcone based hybrids (8-22) and their antimalarial efficacy against both chloroquine-susceptible (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Most of the compounds showed enhanced antimalarial activity as compared to chloroquine in chloroquine-resistant (K1) strain of Plasmodium falciparum. Furthermore, to unfold the mechanism of action of these synthesized hybrid molecules, we carried out hemin dependent studies, in which three compounds were found to be active.

Synthesis and biological evaluation of a new class of 4-aminoquinoline-rhodanine hybrid as potent anti-infective agents.

Synthesis of novel 4-aminoquinoline-rhodanine hybrid using inexpensive starting materials via easy to operate methodology, and their biological activity is reported. All the compounds were screened for their in vitro antimalarial activity against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum, and their cytotoxicity toward VERO cell line. Compounds 9, 19, 21 and 23 exhibited excellent antimalarial activity with IC50 value ranging from 13.2 to 45.5 nM against chloroquine-resistant (K1) strain. Biochemical studies revealed that inhibition of hemozoin formation is the primary mechanism of action of these analogs for their antimalarial activity. Additionally, some derivatives (14, 18 and 26) of this series also exhibited the antimycobacterial activity against H37Rv strain of Mycobacterium tuberculosis with MIC value of 6.25 μM.

Isolation and identification of β-hematin inhibitors from Flacourtia indica as promising antiplasmodial agents

An ethanolic extract (A001) of the leaves and twigs of Flacourtia indica (Burm.f.) Merr., was purified to give a new phenolic glycoside, 2-(2-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol (1) together with poliothrysoside (2), catechin-[5,6-e]-4β-(3,4-dihydroxyphenyl)dihydro-2(3H)-pyranone (3), 2-(6-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol (4), chrysoeriol-7-O-β-D-glucopyranoside (5), and mururin A (6). Compound 6 significantly inhibited the in vitro growth of both a chloroquine-sensitive (3D7) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. It forms a complex with hematin and inhibits β-hematin formation, suggesting that this compound act on a heme polymerization target.

Synthesis of 4-amino-5-cyano-2, 6-Disubstituted Pyrimidines as a Potential Antifilarial DNA Topoisomerase II Inhibitors

A novel series of 4-amino-5-cyano-2, 6-disubstituted pyrimidines have been synthesized and evaluated for their in vitro antifilarial DNA topoisomerase II activity against filarial parasite Setaria Cervi. In particular compounds bearing 4-chloro-phenyl substitutent at position-6, exhibited strong inhibition at 40 microg/mL and 5 microg/mL concentration. The present study based on the biological results obtained, suggests that the nature of substitutent at position-4 in the phenyl ring directly affects DNA topoisomerase II inhibitory activity. Most of the compounds have shown better topoisomerase II inhibitory activity than the standard antifilarial drug (DEC) and the topoisomerase II inhibitors (Novobiocin, Nalidixic acid).