Mahabir Parshad Kaushik

Thiourea based novel chromogenic sensor for selective detection of fluoride and cyanide anions in organic and aqueous media

Novel chromogenic thiourea based sensors 4,4-bis-[3-(4-nitrophenyl) thiourea] diphenyl ether 1 and 4,4-bis-[3-(4-nitrophenyl) thiourea] diphenyl methane 2 having nitrophenyl group as signaling unit have been synthesized and characterized by spectroscopic techniques and X-ray crystallography. The both sensors show visual detection, UV-vis and NMR spectral changes in presence of fluoride and cyanide anions in organic solvent as well as in aqueous medium. The absorption spectra indicated the formation of complex between host and guest is in 1:2 stoichiometric ratios.

Synthesis and antimalarial evaluation of 1, 3, 5-trisubstituted pyrazolines

A series of 1,3,5-trisubstituted pyrazolines were synthesized and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (MRC-02) as well as chloroquine resistant (RKL9) strains of Plasmodium falciparum. The activity was at nano molar concentration. beta-hematin formation inhibition activity (BHIA(50)) of the pyrazolines were determined and correlated with antimalarial activity. A reasonably good correlation (r=0.62) was observed between antimalarial activity (IC(50)) and BHIA(50). This suggests that antimalarial mode of action of this class of compounds appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. Some of the compounds were showing better antimalarial activity than chloroquine against resistant strain of P. falciparum and were also found active in the in vivo experiment.

Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids

AbstractSynthesis and evaluation of the antimalarial activity of new pyridine quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described. Two novel pyridine quinoline hybrid molecules and one bisquinoline molecule were synthesized and purified by column chromatography and evaluated for antimalarial and haem polymerization inhibition (HPIA) activities. The molecules were found to be very good haem polymerization inhibitors but showed poor antimalarial activity. This was attributed to their low vacuole accumulation ratio (VAR) in comparison to chloroquine. These molecules can be used as templates for designing new antimalarials targeting haem detoxification pathway of malaria parasite.Graphical AbstractSynthesis and antimalarial evaluation of novel pyridine quinoline hybridsn B.N Acharya, D. Thavaselvam# and M.P Kaushik*n Discovery Centre, Process Technology Development DivisionDefence R & D Establishment, Jhansi Road, Gwalior-474002 (MP) INDIAn #Division of Microbiology, Defence Research and Development Establishment,Gwalior-474002, Indiann Synthesis and evaluation of antimalarial activity of new pyridine–quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described.

Pharmacophore based discovery of potential antimalarial agent targeting haem detoxification pathway

Pharmacophore hypotheses were generated from molecules having putative antimalarial activities targeting haem detoxification pathway of malarial parasite. A training set consisting of 33 compounds, whose activities were evaluated for haem polymerization inhibition and against chloroquine resistant (K1) strain of Plasmodium falciparum, was optimized to generate hypotheses. The hypothesis showing optimum correlation between actual and estimated activities was validated by Fischers randomization test at 95% confidence level and used as a model to screen our in-house compound database. Nicotinic acid [trans-3-(4-ethoxy-3-methoxy-phenyl)-1-(4-hydroxy-phenyl)-allylidene]-hydrazide (ALH5) was obtained as a hit. The compound was synthesized and evaluated against chloroquine sensitive (MRC-02) and resistant (RKL9) strains of malarial parasite P. falciparum. The compound showed antimalarial activity in nanomolar range and was found comparable with chloroquine.

Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE)

A series of bis-quaternary pyridinium derivatives 3a-3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE.

In vivo antimalarial evaluation of Gomphostenins.

AIM OF THE STUDYnThe present study aims to evaluate the in vivo antimalarial potential of the leaf extract of Gomphostemma niveum and two new compounds; named as Gomphostenin (GN-6) and acetyl Gomphostenin (GN-10) isolated and purified from this plant against Plasmodium berghei in mice.nnnMATERIALS AND METHODSnThe blood schizontocidal activity was performed in early infection of Plasmodium berghei and also in established infection of Plasmodium berghei. The mice were orally administrated with various doses of water and chloroform extracts of leaves of Gomphostemma niveum (GN-W and GN-C, 300, 400 and 500 mg/kg/day), GN-6 and GN-10 (50, 100, 150 and 200mg/kg/day). Chloroquine (8 mg/kg) used as a positive control, while an equal volume of saline plus 0.5% tween-80 was used as a negative control.nnnRESULTSnGN-W, GN-C and pure compounds (GN-6 and GN-10) produced a dose dependent chemosuppression effect at various dose levels. GN-10 exhibited highest percent of chemosuppression i.e. 92.65% at a dose level of 200mg/kg/day. In case of curative test, the survival period of the parasitized infected mice was significantly prolonged at 200mg/kg dose of GN-10.nnnCONCLUSIONSnThe studies have indicated that clerodane class of diterpenes GN-6 and GN-10 certainly holds great promise for malaria control and will be useful in antimalarial chemotherapy.

Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway

Pharmacophore hypotheses were developed for molecules having antimalarial activities targeting the haem detoxification pathway of the malaria parasite. A training set consisting of 23 compounds was selected to generate these hypotheses, and their activities were evaluated for haem polymerization inhibition and against chloroquine-sensitive (3D7) as well as chloroquine-resistant (K1) strains of p. falciparum. The models were cross-validated by Fischer’s randomization test at a 95% confidence level. The model developed against chloroquine-resistant malaria parasites was found to yield the best predictions among the three models.

Efficient oxidation of sulfur mustard and its simulants using N-tert-butyl-N-chlorocyanamide

Abstract N‐tert‐Butyl‐N‐chlorocyanamide reacts with sulfur mustard instantaneously to give a corresponding nontoxic sulfoxide in quantitative yield. The transformation is selective and takes place in semi‐aqueous medium (CH3CN/H2O, 1∶1), even at subzero temperatures.

Synthesis and in vitro kinetic study of novel mono-pyridinium oximes as reactivators of organophosphorus (OP) inhibited human acetylcholinesterase (hAChE)

A series of mono pyridinium oximes linked with arenylacetamides as side chains were synthesized and their in vitro reactivation potential was evaluated against human acetylcholinesterase (hAChE) inhibited by organophosphorus inhibitors (OP) such as sarin, VX and tabun. The reactivation data of the synthesized compounds were compared with those obtained with standard reactivators such as 2-PAM and obidoxime. The dissociation constant (KD) and specific reactivity (kr) of the oximes were also determined by performing reactivation kinetics against OP inhibited hAChE. Among the synthesized compounds, oximes 1-(2-(4-cyanophenylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (12a) and 4-((hydroxyimino)methyl)-1-(2-(4-methoxyphenylamino)-2-oxoethyl)pyridinium chloride (2a) were found most potent reactivators for hAChE inhibited by sarin. In case of VX inhibited hAChE majority of the oximes have shown good reactivation efficacies. Among these oximes 1-(2-(benzylamino)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium chloride (18a), 4-((hydroxyimino)methyl)-1-(2-(4-(methoxycarbonyl)phenylamino)-2-oxoethyl)pyridinium-chloride (14a) and 12a were found to surpass the reactivation potential of 2-PAM and obidoxime. However, the synthesized oximes showed marginal reactivation efficacies in case of tabun inhibited hAChE. The pKa value of the oximes were determined and correlated with their observed reactivation potential.

Antimalarial activity of Gomphostemma crinitum leaf extracts

AbstractAntimalarial efficacy of Gomphostemma crinitum leaf extracts were studied inxa0vitro against the chloroquine-sensitive MRC-02 strain of Plasmodium falciparum. The CHCl3 extract (IC50 37.28xa0μg/mL) was found to be better than the aqueous extract (IC50 111.4xa0μg/mL). The major compound present in CHCl3 extract was coded as GC-7 (12,17-diacetoxy, 15-hydroxy, 2-oxo, 3, 13 E (14)-diene clerodane). Seasonal variation of GC-7 was studied and correlated to the antimalarial efficacy of the crude extracts of leaves collected in different months. GC-7 was found to be the only regular compound present in G.crinitum leaves throughout the year. A good correlation between antimalarial efficacy (IC50 9.3xa0μg/mL) and concentration of GC-7 in crude extracts was observed. The mode of action of GC-7 was found to be different from that of chloroquine.Graphical AbstractAntimalarial activity of Gomphostemma crinitum leaf extractsB.N Acharya, Deepika Saraswat and M.P Kaushik*n Discovery Centre, Process Technology Development DivisionDefence R & D Establishment, Jhansi Road, Gwalior-474002 (MP) INDIAn #Entomology division, Defence Research and Development Establishment,Gwalior-474002, Indiann Antimalarial activity of chloroform extract of G. crinitum leaves and an isolated compound GC-7 (12,17-diacetoxy,15-hydroxy,2-oxo,3,13 E (14)-diene clerodane) against a chloroquine susceptible strain of Plasmodium falciparum is described.