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Upadhayaya, Ram Shankar
Publications (2 of 2) Show all publications
Upadhayaya, R. S., Dixit, S. S., Földesi, A. & Chattopadhyaya, J. (2013). New antiprotozoal agents: Their synthesis and biological evaluations. Bioorganic & Medicinal Chemistry Letters, 23(9), 2750-2758
Open this publication in new window or tab >>New antiprotozoal agents: Their synthesis and biological evaluations
2013 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 23, no 9, p. 2750-2758Article in journal (Refereed) Published
Abstract [en]

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 mu M. 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. 

Keywords
Antiprotozoal agents, Trypanosoma, Leishmania, Parasite inhibitors, Conformationally constrained quinoline
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-200043 (URN)10.1016/j.bmcl.2013.02.054 (DOI)000317333900054 ()
Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
Dixit, S. S., Upadhayaya, R. S. & Chattopadhyaya, J. (2012). New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines. Organic and biomolecular chemistry, 10(30), 6121-6129
Open this publication in new window or tab >>New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines
2012 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 10, no 30, p. 6121-6129Article in journal (Refereed) Published
Abstract [en]

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'-CH2-O-2' bridge (Fig. 2) 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 IC50 = 0.25-0.51 mu M. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC50 = 0.25 mu M) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC50 >4 mu M) and in diploid human fibroblasts MRC-5 cell lines (CC50 4 mu M). 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.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-179236 (URN)10.1039/c2ob25879j (DOI)000306276800062 ()
Available from: 2012-12-13 Created: 2012-08-10 Last updated: 2017-12-07Bibliographically approved
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