Novel Betulin Derivatives as Antileishmanial Agents with Mode of Action Targeting Type IB DNA Topoisomerase

ABSTRACT Toward developing antileishmanial agents with mode of action targeted to DNA topoisomerases of Leishmania donovani, we have synthesized a large number of derivatives of betulin. The compound, a natural triterpene isolated from the cork layer of Betula spp. plants exhibits several pharmacological properties. Three compounds (disuccinyl betulin, diglutaryl dihydrobetulin, and disuccinyl dihydrobetulin) inhibit growth of the parasite as well as relaxation activity of the enzyme type IB topoisomerase [Leishmania donovani topoisomerase I (LdTOP1LS)] of the parasite. Mechanistic studies suggest that these compounds interact with the enzyme in a reversible manner. The stoichiometry of these compounds binding to LdTOP1LS is 1:1 (mole/mole) with a dissociation constant on the order of ϳ10 Ϫ6 M. Unlike CPT, these compounds do not stabilize the cleavage complex; rather, they abrogate the covalent complex formation. In processive mode of relaxation assay condition, these compounds slow down the strand rotation event, which ultimately affects the relaxation of supercoiled DNA. It is noteworthy that these compounds reduce the intracellular parasite burden in macrophages infected with wild-type L. donovani as well as with sodium antimony gluconate resistant parasite (GE1). Taken together, our data suggest that these betulin derivatives can be exploited as potential drug candidates against threatening drug resistant leishmaniasis

New iridoid glucoside from <i>Picrorhiza kurroa </i>Royle ex Benth.

1023-1025Picrorhiza kurroa Royle ex Benth, commonly known as kutki is used as a crude drug reported in Indian pharmacopoeia. Acetyl derivative of a new iridoid glucoside, picroside V (6-m-methoxybenzoyl catalpol) along with three known iridoid glucosides picroside I, picroside II and catalpol have been isolated from the roots of Picrorhiza kurroa Royle ex Benth

One-Pot Synthesis of the Naturally Occurring Dimeric Carbazole Alkaloid Murranimbine and its Analogue

Murranimbine, a naturally occurring dimeric carbazole alkaloid, isolated from the root bark of Murraya euchrestfolia was synthesized in one step by the application of Lewis acid (BF3–Et2O) on its monomer girinimbine. A new dimer of koenidine was also synthesized following the same procedure. Structures of these dimeric carbazole alkaloids were determined by detailed spectral analysis

<span style="font-size:14.0pt;line-height: 115%;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; color:black;mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language: HI" lang="EN-IN">Bacopasaponin H: A pseudojujubogenin glycoside from <i>Bacopa monniera</i></span>

1802-1804A new dammarane-type pseudojujubogenin glycoside hacopasaponin H has been isolated from the reputed Indian medicinal plant Bacopa monniera and characterized as 3-O-[α-1-arabinopyranosyl] pseudojujubogenin by spectral and chemical studies

Allylic Hydroxylation Through Acid Catalysed Epoxy Ring Opening of Betulinic Acid Derivatives

Acid catalysed epoxy ring opening of several lupane type triterpenoids leads to unusual allylic hydroxylation. The reaction involves the formation of epoxide by m-chloroperbenzoic acid followed by the treatment of mineral acid. The simple methodology finds utility to introduce a hydroxyl function at the allylic position in these triterpenoids, which is otherwise quite difficult

Swertane Triterpenoids from Swertia-Chirata

Two novel triterpenes belonging to swertane skeleton, besides gammacer-16-en-3/B-ol and ZlcrH-hop-22(29)-en-3/B01, of rare occurrence have been isolated from Swertiu chiratu, along with some common triterpenoids. Their structures were established on the basis of spectral and chemical evidence

Evaluation of the in-vivo activity and toxicity of amarogentin, an antileishmanial agent, in both liposomal and niosomal forms

The antileishmanial property of amarogentin, a secoiridoid glycoside isolated from the Indian medicinal plant Swertia chirata, was examined in a hamster model of experimental leishmaniasis. The therapeutic efficacy of amarogentin was evaluated in free and two different vesicular forms, liposomes and niosomes. The amarogentin in both liposomal and niosomal forms was found to be a more active leishmanicidal agent than the free amarogentin; and the niosomal form was found to be more efficacious than the liposomal form at the same membrane microviscosity level. Toxicity studies involving blood pathology, histological staining of tissues and specific enzyme levels related to normal liver function showed no toxicity. Hence, amarogentin incorporated in liposomes or niosomes may have clinical application in the treatment of leishmaniasi

Quercetin Interferes With iron Metabolism in Leishmania donovani and Targets Ribonucleotide Reductase to Exert Leishmanicidal Activity

The possibility of developing antileishmanial drugs was evaluated by intervention in the parasite’s iron metabolism, utilizing quercetin (Qr) under in vivo conditions, and identifying the target of this lipophilic metal chelator against Leishmania donovani. Methods: Interaction between Qr and serum albumin (SA) was studied by using the intrinsic fluorescence of Qr as a probe. The effect of treatment with Qr and SA on the proliferation of amastigotes was determined by evaluating splenic parasite load. Disintegration of parasites in response to combination treatment was assessed from ultrastructural analysis using a transmission electron microscope. Quenching of the tyrosyl radical of ribonucleotide reductase (RR) in treated amastigotes was detected by an electron paramagnetic resonance study. Results: Treatment with a combination of Qr and SA increased bioavailability of the flavonoid and proved to be of major advantage in promoting the effectiveness of Qr towards the repression of splenic parasite load from 75%, P < 0.01 to 95%, P < 0.002. Qr-mediated down-regulation of RR (P < 0.05), catalysing the rate-limiting step of DNA synthesis in the pathogens, could be related to the deprivation of the enzyme of iron which in turn destabilized the critical tyrosyl radical required for its catalysing activity. Conclusions: Results have implications for improved leishmanicidal action of Qr in combination with SA targeting RR and suggest future drug design based on interference with the parasite’s iron metabolism under in vivo conditions