Publications by authors named "Shailesh Dixit"

10 Publications

  • Page 1 of 1

New antiprotozoal agents: their synthesis and biological evaluations.

Bioorg Med Chem Lett 2013 May 22;23(9):2750-8. Epub 2013 Feb 22.

Program of Chemical Biology, Institute of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden.

Here we report identification of new lead compounds based on quinoline and indenoquinolines with variable side chains as antiprotozoal agents. Quinolines 32, 36 and 37 (Table 1) and indenoquinoline derivatives 14 and 23 (Table 2) inhibit the in vitro growth of the Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense subspecies and Leishmania infantum with IC50=0.25 μM. These five compounds have superior activity to that of the front-line drugs such as benznidazole, nifurtimox and comparable to amphotericin B. Thus these compounds constitute new 'leads' for further structure-activity studies as potential active antiprotozoal agents.
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http://dx.doi.org/10.1016/j.bmcl.2013.02.054DOI Listing
May 2013

New parasite inhibitors encompassing novel conformationally-locked 5'-acyl sulfamoyl adenosines.

Org Biomol Chem 2012 Aug 19;10(30):6121-9. Epub 2012 Jun 19.

Program of Chemical Biology, Institute of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden.

We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH(2)-O-2' bridge () across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC(50) = 0.25-0.51 μM. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC(50) = 0.25 μM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC(50) >4 μM) and in diploid human fibroblasts MRC-5 cell lines (CC(50) 4 μM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.
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http://dx.doi.org/10.1039/c2ob25879jDOI Listing
August 2012

Guillain-Barre syndrome occurring during dengue fever.

J Indian Med Assoc 2011 Sep;109(9):675, 682

Department of Neurology, BMRC, SMS Medical College, Jaipur 302004.

Various types of neurological manifestations are described in dengue fever, of which peripheral neuropathy is rarely reported. We are reporting such a case that presented with three days' history of fever and weakness of all the four limbs of two days' duration. On investigations it turned out to be acute motor sensory axonal neuropathy (AMSAN) type of Guillain-Barre syndrome with decrease platelet counts and positive serology for dengue. All other causes of acute polyneuropathy were ruled out by history and relevant investigations. Patient improved with intravenous immunoglobulin and other supportive therapy.
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September 2011

Carba-LNA-5MeC/A/G/T modified oligos show nucleobase-specific modulation of 3'-exonuclease activity, thermodynamic stability, RNA selectivity, and RNase H elicitation: synthesis and biochemistry.

J Org Chem 2011 Jun 4;76(11):4408-31. Epub 2011 May 4.

Institute of Molecular Medicine, International Biotech Park, Tal Mulshi, Hinjewadi, Pune, India.

Using the intramolecular 5-exo-5-hexenyl radical as a key cyclization step, we previously reported an unambiguous synthesis of carba-LNA thymine (cLNA-T), which we subsequently incorporated in antisense oligonucleotides (AON) and investigated their biochemical properties [J. Am. Chem. Soc.2007, 129 (26), 8362-8379]. These cLNA-T incorporated oligos showed specific RNA affinity of +3.5-5 °C/modification for AON:RNA heteroduplexes, which is comparable to what is found for those of LNAs (Locked Nucleic Acids). These modified oligos however showed significantly enhanced nuclease stability (ca. 100 times more) in the blood serum compared to those of the LNA modified counterparts without compromising any RNase H recruitment capability. We herein report the synthesis of 5-methylcytosine-1-yl ((Me)C), 9-adeninyl (A), and 9-guaninyl (G) derivatives of cLNA and their oligonucleotides and report their biochemical properties as potential RNA-directed inhibitors. In a series of isosequential carba-LNA modified AONs, we herein show that all the cLNA modified AONs are found to be RNA-selective, but the magnitude of RNA-selectivity of 7'-R-Me-cLNA-G (cLNA-G) (ΔT(m) = 2.9 °C/modification) and intractable isomeric mixtures of 7'-(S/R)-Me-cLNA-T (cLNA-T, ΔT(m) = 2.2 °C/modification) was found to be better than diastereomeric mixtures of 7'-(S/R)-Me-cLNA-(Me)C with trace of cENA-(Me)C (cLNA-(Me)C, ΔT(m) = 1.8 °C/modification) and 7'-R-Me-cLNA-A (cLNA-A, ΔT(m) = 0.9 °C/modification). cLNA-(Me)C modified AONs however exhibited the best nuclease stability, which is 4-, 7-, and 20-fold better, respectively, than cLNA-T, cLNA-A, and cLNA-G modified counterparts, which in turn was more than 100 times stable than that of the native. When the modification sites are appropriately chosen in the AONs, the cLNA-A, -G, and -(Me)C modified sites in the AON:RNA hybrids can be easily recognized by RNase H, and the RNA strand of the hybrid is degraded in a specific manner, which is important for the design of oligos for therapeutic purposes. The cLNA-(Me)C modified AON/RNA, however, has been found to be degraded 4 times faster than cLNA-A and G modified counterparts. By appropriately choosing the carba-LNA modification sites in AON strands, the digestion of AON:RNA can be either totally repressed or be limited to cleavage at specific sites or at a single site only (similar to that of catalytic RNAzyme or DNAzyme). Considering all physico- and biochemical aspects of cLNA modified oligos, the work suggests that the cLNA modified antisense oligos have the potential of being a promising therapeutic candidate due to their (i) higher nucleobase-specific RNA affinity and RNA selectivity, (ii) greatly improved nuclease stability, and (iii) efficient RNase H recruitment capability, which can induce target RNA cleavage in a very specific manner at multiple or at a single site, in a designed manner.
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http://dx.doi.org/10.1021/jo200073qDOI Listing
June 2011

Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives.

Eur J Med Chem 2011 Apr 3;46(4):1306-24. Epub 2011 Feb 3.

Institute of Molecular Medicine, Pune 411 057, India.

Recently we have reported anti-TB properties of a new class of conformationally-constrained indeno[2,1-c]quinolines, which are although considerably active (MIC 0.39-0.78 μg/mL) suffered from intense solubility problems. We thought of improving their bioavailability by prodrugs approach. Accordingly esters of the "Lead" indeno[2,1-c]quinolines 1, 15 and 27 derivatives were synthesized and their prodrug nature at the physiological pH were confirmed. Prodrugs were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MABA assay to show that they have 2- to 4-fold improved anti-TB activities, increased aqueous solubility and superior selectivity index over their respective parent compounds. MIC of these prodrugs was in the range of <0.20-6.0 μg/mL, and in general, no cytotoxicity was observed in VERO cells.
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http://dx.doi.org/10.1016/j.ejmech.2011.01.053DOI Listing
April 2011

Conformationally-constrained indeno[2,1-c]quinolines--a new class of anti-mycobacterial agents.

Org Biomol Chem 2010 May 15;8(9):2180-97. Epub 2010 Mar 15.

Institute of Molecular Medicine, Pune 411 057, India.

The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new conformationally-constrained indeno[2,1-c]quinoline analogs (Fig. 1), by retaining the biologically significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class of conformationally-constrained compounds has been designed such that their conformational flexibility across C4-C2' is diminished to nil by covalently locking the C4 center of the quinoline moiety in the SW hemisphere with the C2' center of the phenyl ring in the NW hemisphere, thereby decreasing the entropic penalty for their complex formation within the target protein, which will in turn give improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of 0.39 microg mL(-1) (1 microM) and 0.78 microg mL(-1) (2 microM) respectively.
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http://dx.doi.org/10.1039/b924102gDOI Listing
May 2010

Novel quinoline and naphthalene derivatives as potent antimycobacterial agents.

Eur J Med Chem 2010 May 20;45(5):1854-67. Epub 2010 Jan 20.

Institute of Molecular Medicine, Pune 411 057, Maharashtra, India.

We have designed and synthesized both the quinoline and naphthalene based molecules influenced by the unique structural make-up of mefloquine and TMC207, respectively. These compounds were evaluated for their anti-mycobacterial activity against drug sensitive Mycobacterium tuberculosis H37Rv in vitro at single-dose concentration (6.25 microg/mL). The compounds 22, 23, 26 and 27 inhibited the growth of M. tuberculosis H37Rv 99%, 90%, 98% and 91% respectively. Minimum inhibitory concentration of compounds 22, 23, 26 and 27 was found to be 6.25 microg/mL. Our molecular modeling and docking studies of designed compounds showed hydrogen bonding with Glu-61, Tyr-64 and Asn-190 amino acid residues at the putative binding site of ATP synthase, these interactions were coherent as shown by Mefloquine and TMC207, where hydrogen bonding was found with Tyr-64 and Glu-61 respectively. SAR analysis indicates importance of hydroxyl group and nature of substituents on piperazinyl-phenyl ring was critical in dictating the biological activity of newly synthesized compounds.
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http://dx.doi.org/10.1016/j.ejmech.2010.01.024DOI Listing
May 2010

Design, synthesis and biological evaluation of novel triazole, urea and thiourea derivatives of quinoline against Mycobacterium tuberculosis.

Bioorg Med Chem 2009 Jul 5;17(13):4681-92. Epub 2009 May 5.

Institute of Molecular Medicine, Pune, India.

A new series of 20 quinoline derivatives possessing triazolo, ureido and thioureido substituents have been synthesized and their antimycobacterial properties have been evaluated. Compounds 10, 22 and 24 inhibited Mycobacterium tuberculosis H37Rv up to 96%, 98% and 94% respectively, at a fixed concentration of 6.25 microg/mL. Minimum inhibitory concentration of 3.125 microg/mL was obtained for compound 10 and 24, while for compound 22 it was 6.25 microg/mL. Molecular docking calculations suggest critical hydrogen bonding and electrostatic interactions between polar functional groups (such as quinoline-nitrogen, urea-carbonyl and hydroxyl) of anti-mycobacterial (anti-TB) compounds and amino acids (Arg186 and Glu61) of ATP-synthase of M. tuberculosis, could be the probable reason for observed anti-mycobacterial action.
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http://dx.doi.org/10.1016/j.bmc.2009.04.069DOI Listing
July 2009

Design, synthesis, biological evaluation and molecular modelling studies of novel quinoline derivatives against Mycobacterium tuberculosis.

Bioorg Med Chem 2009 Apr 21;17(7):2830-41. Epub 2009 Feb 21.

Institute of Molecular Medicine, Pune 411 057, India.

We herein describe the synthesis and antimycobacterial activity of a series of 27 different derivatives of 3-benzyl-6-bromo-2-methoxy-quinolines and amides of 2-[(6-bromo-2-methoxy-quinolin-3-yl)-phenyl-methyl]-malonic acid monomethyl ester. The antimycobacterial activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv for nine consecutive days upon a fixed concentration (6.25 microg/mL) at day one in Bactec assay and compared to untreated TB cell culture as well as one with isoniazide treated counterpart, under identical experimental conditions. The compounds 3, 8, 17 and 18 have shown 92-100% growth inhibition of mycobacterial activity, with minimum inhibitory concentration (MIC) of 6.25 microg/mL. Based on our molecular modelling and docking studies on well-known diarylquinoline antitubercular drug R207910, the presence of phenyl, naphthyl and halogen moieties seem critical. Comparison of docking studies on different stereoisomers of R207910 as well as compounds from our data set, suggests importance of electrostatic interactions. Further structural analysis of docking studies on our compounds suggests attractive starting point to find new lead compounds with potential improvements.
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http://dx.doi.org/10.1016/j.bmc.2009.02.026DOI Listing
April 2009

Wilson's disease presenting as isolated obsessive-compulsive disorder.

Indian J Med Sci 2007 Nov;61(11):607-10

Department of Neurology, SMS Medical College, Jaipur, Rajasthan, India.

Wilson's disease (WD) is a genetic neurodegenerative disorder; it exhibits wide heterogeneity in symptoms and usually presents with liver disease and/ or neuropsychiatric manifestations. The common neurological manifestations observed are dysarthria, gait disturbance, dystonia, rigidity, tremor, dysphagia and chorea. The frequent psychiatric manifestations reported are personality and mood changes, depression, phobias, cognitive impairment, psychosis, anxiety, compulsive and impulsive behavior. Isolated obsessive-compulsive disorder (OCD) is a rare presentation of WD. Reported herein is a case of a 17-year-old boy with isolated OCD. He presented to the psychiatrist with symptoms of contamination obsessions and washing compulsions, along with compulsion of repeated feet tapping and was treated with adequate doses of fluoxetine for 6 months but did not improve. Later on, he was diagnosed as a case of WD and showed improvement with chelating and behavior therapy. This implies the importance of the occurrence of isolated psychological symptoms in WD.
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http://dx.doi.org/10.4103/0019-5359.37047DOI Listing
November 2007