| 1. |
- Dixit, Shailesh S., et al.
(författare)
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New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines
- 2012
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 10:30, s. 6121-6129
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Dutta, Suman, et al.
(författare)
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Carba-LNA modified siRNAs targeting HIV-1 TAR region downregulate HIV-1 replication successfully with enhanced potency
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:3, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- The conformationally-locked carbocyclic nucleosides carbaLNA ("jcLNA") (Gagnon et al., Biochemistry, 2010, 49, 10166; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362; Xu et al., J. Org. Chem., 2009, 74, 6534; Zhou and Chattopadhyaya, J. Org. Chem., 2010, 75, 2341; Zhou et al., J. Org. Chem., 2009, 74, 118) are chemically engineered by fusing a carbocyclic ring at the C2' to C4' chiral centres in a stereospecific manner at the alpha-face of the pentose-sugar of the native nucleosides. The benefit of the chemically-modified oligonucleotides with the jcLNA scaffold has been shown to be their uniquely enhanced nuclease resistance in the blood serum as well as their improved RNase H recruitment capability to cleave the target RNA in the hybrid antisense-RNA duplex when used as an antisense agent, compared to those of locked nucleic acid (LNA) modified counterparts. Herein we report the relative inhibition efficiency of HIV-1 by jcLNA modified siRNAs targeting TAR region compared to those of the LNA counterparts, in that the former were found to exhibit improved silencing efficiency and displayed enhanced stability in human serum with negligible cytotoxicity compared to those of the latter. A single jcLNA substitution as the 3'-overhang of the guide strand displayed near native-like IC50 value (of 4.01 +/- 0.87 nM compared to the nearly two-fold higher IC50 value of 7.15 +/- 1.57 nM for LNA modified counterparts, and of the native siRNA of 1.84 +/- 0.16 nM) and significantly higher hp value for the stability in serum (11.9 h for jcLNA, 6.8 h for LNA and 3.0 h for native), thereby showing that the efficiency of jcLNA-modified-siRNAs is supported by stability without compromising the native-like efficiency and target RNA recognition and subsequent down-regulation. Amongst all the modified siRNAs so far used to target HIV-1 TAR region, the best IC50 value was obtained for the doubly-modified siRNA in which jcLNA substitution was introduced both at position 1 and 20 of the antisense strand (T-1 + T-20, i.e. jcLNA11 which showed IC50 value of 0.54 +/- 0.14 nM). The IC50 of this doubly-modified siRNA was more than three-fold lower than that of the native and two-fold lower than that of LNA modified counterpart, i.e. LNA12: IC50: 1.13 +/- 0.27 nM. Hence the strategy to chemically modify the native siRNAs by substitution with the jcLNA can be considered as a significant development, leading to both enhanced siRNA efficiency and serum stability over that of the native.
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| 3. |
- Dutta, Suman, et al.
(författare)
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The R-diastereomer of 6 '-O-toluoyl-carba-LNA modification in the core region of siRNA leads to 24-times improved RNA silencing potency against the HIV-1 compared to its S-counterpart
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:11, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- The modified siRNA with pure [6'(S)-O-(p-toluoyl)-7'(S)-methyl]-carba-LNA [6'(S)-O-toluoyl-jcLNA] at position T(13) displayed an IC(50) of 79.8 nM, which has been found to be nearly 24-times less potent as a HIV-1 RNAi silencing agent against TAR RNA than that of the corresponding pure [6'(R)-O-(ptoluoyl)-7'(S)-methyl]jcLNA [6'(R)-O-(p-toluoyl)-jcLNA] counterpart [IC(50) 3.3 nM]. The later [6'(R)-O-(p-toluoyl)-jcLNAl-modified siRNAs have been found to be nearly 2-fold more efficient as a silencing agent than the corresponding 6'-deoxy-jcLNA modified siRNA [IC(50) 8.1 nM], and also nearly 3-fold more effective as a silencing agent than that of LNA-modified siRNA [IC(50) 11.7 nM], thereby showing that the 6'-carbon center in the jcLNA-modified siRNA in the core region is relatively more exposed to the Ago protein in the RISC with a clear chirality preference for the siRNA cleavage reaction. It is noteworthy that the IC(50) of jcLNA-modified siRNAs are very comparable to that of the native siRNA [1.8 nM]. The jcLNA derivatized siRNAs, however, have a clear advantage of being, in general, considerably more stable in human serum. The main structural difference in duplexes of the antisense strand of the 6'(R or S)-O-(p-toluoyl)-jcLNA modified siRNA and target RNA duplex is found to be the spatial orientation of the 6'(R)-O-toluoyl group, which is exposed towards the edge of the duplex backbone, while the 6'(S) makes the minor groove relatively inaccessible for the Ago protein in the RISC. Clearly, any further C6'-modification in jcLNA-modified siRNAs with any hydrophobic group for tighter binding and cleavage or for cross-linking in the core region should preferably be done in the 6'(R)-stereochemistry.
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| 4. |
- Upadhayaya, Ram Shankar, et al.
(författare)
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Conformationally-constrained indeno[2,1-c]quinolines : a new class of anti-mycobacterial agents
- 2010
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 8:9, s. 2180-2197
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Tidskriftsartikel (refereegranskat)abstract
- 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 mu g mL(-1) (1 mu M) and 0.78 mu g mL(-1) (2 mu M) respectively.
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| 5. |
- Upadhayaya, Ram Shankar, et al.
(författare)
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New antiprotozoal agents : Their synthesis and biological evaluations
- 2013
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2750-2758
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Upadhayaya, Ram Shankar, et al.
(författare)
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Novel quinoline and naphthalene derivatives as potent antimycobacterial agents
- 2010
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:5, s. 1854-1867
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Tidskriftsartikel (refereegranskat)abstract
- 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 mu g/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 mu g/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. (C) 2010 Elsevier Masson SAS. All rights reserved.
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| 7. |
- Upadhayaya, Ram Shankar, et al.
(författare)
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Synthesis and antimycobacterial activity of prodrugs of indeno[2,1-c]quinoline derivatives
- 2011
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 46:4, s. 1306-1324
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Tidskriftsartikel (refereegranskat)abstract
- 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 mu g/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 mu g/mL and in general, no cytotoxicity was observed in VERO cells.
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| 8. |
- Upadhayaya, Ram Shankar, et al.
(författare)
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Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their anti-mycobacterial properties
- 2010
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 8:24, s. 5661-5673
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Tidskriftsartikel (refereegranskat)abstract
- Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 mu g mL(-1) and 0.78 mu g mL(-1), respectively)(14) with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c] quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 mu g mL(-1). The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 mu g mL(-1) (0.89 mu M and 1 mu M, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB.
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