K. M. Muraleedharan

Bio: K. M. Muraleedharan is an academic researcher from Indian Institute of Technology Madras. The author has contributed to research in topic(s): Artemisinin & Carboxylic acid. The author has an hindex of 12, co-authored 47 publication(s) receiving 751 citation(s). Previous affiliations of K. M. Muraleedharan include University of Mississippi & Indian Institute of Chemical Technology.

Halo- and selenolactonisation: the two major strategies for cyclofunctionalisation

Abstract: At the turn of the 20th century, Bougoult made a detailed and systematic study of the conversion of b,g- and g,d-unsaturated carboxylic acids to iodolactones with iodine in aqueous NaHCO3. He showed that, when the double bond was further removed from the carboxylic acid functionality, no reaction took place. He considered that these reactions involved the addition of nascent hypoiodous acid, followed by lactonisation of the resulting hydroxy acid.1 Intervening developments in this area as well as in mechanistic studies enabled van Tamelen and Shamma to propose, in 1954, the currently accepted view of this process, namely that halolactonisation arise by the intramolecular carboxylic acid-mediated opening of the initially-formed halonium ion intermediate.

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

Abstract: Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Progress in the development of peroxide-based anti-parasitic agents.

Abstract: Progress made in the past decade pertaining to the development of anti-parasitic agents based on artemisinin is presented. Apart from discussions on important derivatives obtained through functionalization at the C-3, C-9, C-10 and O-11 positions of artemisinin, an outline on its seco analogs and artemisinin bundles are given for a broader perspective on structure-activity relationships. Success with synthetic peroxides, drug-hybrid approaches, broad-spectrum anti-infective properties of peroxide compounds and a survey on peroxide-containing natural products other than artemisinin with available biological data are included to highlight recent trends and avenues for future research. A supplementary material with details on the biological properties of a larger collection of molecules belonging to the above structural classes is also given for reference.

Transformation of artemisinin by Cunninghamella elegans

Abstract: Semi-synthetic derivatives of the anti-malarial drug artemisinin hold great promise in the search for an effective and economical treatment of chloroquine-resistant forms of malaria. Unfortunately, synthetic functionalization of the artemisinin skeleton is often tedious and/or impractical. We seek to utilize 7β-hydroxyartemisinin, obtained from microbial transformation, as a semi-synthetic precursor for the synthesis of novel 7β-substituted artemisinin anti-malarial agents. Here we employ liquid cultures of Cunninghamella elegans as a means for the rational and economical bioconversion of artemisinin to 7β-hydroxyartemisinin in 78.6% yield. In addition, there were three other bioconversion products: 7β-hydroxy-9α-artemisinin (6.0%), 4α-hydroxy-1-deoxoartemisinin (5.4%), and 6β-hydroxyartemisinin (6.5%).

Microbial transformation of artemisinin to 5-hydroxyartemisinin by Eurotium amstelodami and Aspergillus niger

Abstract: Transformation of the anti-malarial drug artemisinin by the fungi Eurotium amstelodami and Aspergillus niger were investigated. Cultures were grown in sucrose/malt broth with artemisinin for 14 days and extracted with ethyl acetate. Extracts were characterized by liquid chromatography. Two metabolites from each fungal extract were isolated and identified using mass spectrometry and nuclear magnetic resonance. 5β-hydroxyartemisinin and 7β-hydroxyartemisinin were isolated in 63 and 32% yields, respectively, from the extract of E. amstelodami, and 80 and 19%, respectively, from the extract of A. niger.

Peptide-based stimuli-responsive biomaterials

Abstract: This article explores recent advances in the design and engineering of materials wholly or principally constructed from peptides. We focus on materials that are able to respond to changes in their environment (pH, ionic strength, temperature, light, oxidation/reduction state, presence of small molecules or the catalytic activity of enzymes) by altering their macromolecular structure. Such peptide-based responsive biomaterials have exciting prospects for a variety of biomedical and bionanotechnology applications in drug delivery, bio-sensing and regenerative medicine.

Gold(III) Salen complex-catalyzed synthesis of propargylamines via a three-component coupling reaction.

Abstract: [reaction: see text] Propargylamines have been synthesized by a gold(III) salen complex-catalyzed three-component coupling reaction of aldehydes, amines, and alkynes in water in excellent yields at 40 degrees C. With chiral prolinol derivatives as the amine component, excellent diastereoselectivities (up to 99:1) have been attained. This coupling reaction has been applied to the synthesis of propargylamine-modified artemisinin derivatives with the delicate endoperoxide moieties remaining intact. Cytotoxicities with IC(50) values up to 1.1 microM against a human hepatocellular carcinoma cell line (HepG2) were exhibited by these artemisinin derivatives.

Current perspectives on the mechanism of action of artemisinins

Abstract: Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.

Enantioselective bromolactonization of conjugated (Z)-enynes.

Abstract: A catalytic enantioselective syn-1,4-bromolactonization of conjugated (Z)-enynes was reported. Diastereomeric ratios >20:1 and up to 99% enantiomeric excesses were observed. Di-, tri-, and tetra-substituted bromoallenes were prepared together with lactone heterocycles efficiently and stereoselectively. Preliminary investigations suggest that the chiral catalyst may serve as a bifunctional reagent by interacting with both a carboxylic acid nucleophile and NBS electrophile.