Projects to combat infectious diseases
The increase in antibiotic resistance in multitude of various human pathogens entails the necessity of continued drug development. To overcome the problem of multiple drug resistance (MDR) and extensively drug resistant (XDR) and latent strains of Mycobacterium tuberculosis (Mtb) and the virulence of resistance and Gram-negative bacteria, HIV/AIDS and neglected diseases mainly associated to unicellular protozoans like Trypanosoma [human specific Cruzi (chagas disease) and brucei (sleeping sickness) and Leishmania infantum (leishmaniasis)]. We need to validate new classes of drug targets and new chemistry against them. To achieve our goals we aimed to target the following components of the host and the guest 1. Bacterial membrane, 2. Bacterial genome, 3. Bacterial energy pathway, 4. Host cell mycobacterium interactions. In these efforts our research group has published recent papers (2009-2013) PDF 383, 385, 386, 391, 392, 393, 395, 397, 401, 402, 404, 408, 411, 412, 415, 416, have been focused on finding effective antibacterial compounds against drug-resistant, multiple drug resistant (MDR) and especially extensive drug resistant (XDR) tuberculosis.We have explored new class of antimycobacterial agents conformationally-locked indeno[2,1-c]quinolines as antimycobacterials and some other scaffolds as presented below. For more information please write to Prof. Jyoti Chattopadhyaya (firstname.lastname@example.org)
Various New Scaffolds Designed and Explored by us
Our work, as described above, has already led us to International patent [patent No.PCT/SE2009/050008] PDF 385 with definite “Lead” molecules which we are exploiting for new hit-to-lead molecules against TB.
On the topic of anti-TB and
anti-bacterial drug development we have yet published 16
peer-reviewed papers in 2009/2013 (shown
full list of our publication can be seen at www.boc.uu.se),
thereby we are showcasing our track-record and ability to make
progress with our proposed plan for the new drug discovery against
Selected publications on the
subject of anti-TB and drug discovery (2009/2010):
Upadhayaya, V.J. Kishore, V. Nageswar Rao, V. Sharma, S. S.
Dixit and J. Chattopadhyaya.
Design, Synthesis, Biological Evaluation and Molecular modeling
studies of Novel Quinoline Derivatives Against Mycobacterium
tuberculosis. Bioorganic & Medicinal Chemistry, 17,
385. J Chattopadhyaya and RS Upadhyaya. Novel Quinoline, Non-Quinoline and Conformationally constrained Quinoline Derivatives as Anti-Mycobacterial Agents, PCT/SE 2009/050008.
386. RS Upadhayaya, GM. Kulkarni, V. Nageswara Rao, V. J. Kishore, SS Dixit, V. Sharma and J. Chattopadhyaya, Design, Synthesis and biological evaluation of novel triazole, urea and thiourea derivatives of Quinoline against Mycobacterium tuberculosis. Bioorganic & Medicinal Chemistry, 17, 4681-4692 (2009).
391. RS Upadhayaya, SV. Lahore, MP. Sarmah, V. Sharma, SS. Dixit, PD. Shinde, A Y. Sayyed, AM. Vibhute, MM. Shaikh, & J. Chattopadhyaya.Conformationally constrained Indeno[2,1-c]quinolines - A new class of anti-mycobacterial agents. Organic & Biomolecular Chemistry, 8, 2180-2197 (2010).
392. R. S. Upadhayaya, J. K. Vandavasi, R. A. Kardile, S. V. Lahore, S. S. Dixit, H. S. Deokar, P. D. Shinde, M. P. Sarmah and J. Chattopadhyaya, Novel Quinoline and Naphthalene derivatives as potent Antimycobacterial agents. European Journal of Medicinal Chemistry, 45, 1854-1867 (2010).
393. C. Zhou and J. Chattopadhyaya. Why carba-LNA Modified Oligonucleotides Show Considerably Improved 3’-Exonuclease Stability Compared to that of the LNA Modified or the Native Counterparts: A Michaelis-Menten Kinetic Analysis. Journal of Organic Chemistry, 75, 2341-2349 (2010).
394. Mook O.R.F., Vreijling J., Lena-Wengel S., Wengel J., Zhou C., Chattopadhyaya J., Baas F., Fluiter K. In vivo efficacy and off-target effects of Locked Nucleic Acid (LNA) and Unlocked Nucleic Acid (UNA) modified siRNA and small internally segmented interfering RNA (sisiRNA) in mice bearing human tumor xenografts. Artificial DNA: PNA & XNA, 1, 36-44 (2010)
395. J. B. Bramsen, M. M. Pakula, T. B. Hansen, C. Bus, N. Langkjćr, J. Chattopadhyaya, J. W. Engels, P. Herdewijn, J. Wengel and J. Kjems A screen of chemical modifications identifies positionspecific modification by UNA to most potently reduce siRNA off-target effects. Nucleic Acids Research, 38 (17), 5761-5773 (2010)
397. R. S. Upadhayaya, P. D. Shinde, A. Y. Sayyed, S. A. Kadam, A. N. Bawane, A. Poddar, O.Plashkevych, A. Földesi and J. Chattopadhyaya. Synthesis and structure of azole-fused indeno[2,1-c] quinolines and their anti-mycobacterial properties. Organic and Biomolecular Chemistry, 8 (24), 5661–5673 (2010).
401. S. Dutta, N. Bhaduri, N. Rastogi, S. G. Chandel, J. Vandavasi, R. S. Upadhayaya, and J. Chattopadhyaya. The carba-LNA modified siRNAs targeting HIV-1 TAR region downregulates HIV-1 replication successfully withEnhanced Potency. Med. Chem. Comm., 2, 206-216 (2011) Hot article
402. R.S. Upadhayaya, P. D. Shinde, S. A. Kadam, A.N. Bawane,A. Y. Sayyed, R. A. Kardile, P. N. Gitay, S. V. Lahore, S. S. Dixit, A. Földesi, and J. Chattopadhyaya. Synthesis and Antimycobacterial Activity of Prodrugs ofIndeno[2,1-c]quinoline Derivatives. European Journal of Medicinal Chemistry, 46, 1306-1324 (2011).
404. Upadhayaya, R.; Deshpande, S.; Li, Q.; Kardile, R.; Sayyed, A.; Kshirsagar, E.; Salunke, R.; Dixit, S.; Zhou, C.; Földesi, A.; Chattopadhyaya, J. Carba-LNA-5MeC/A/G/T modified Oligos Show Nucleobase-specific Modulation of 3′-Exonuclease Activity, Thermodinamic Stability, RNA-Selectivity and RNAse H Elicitation: Synthesis and Biochemistry. Journal of Organic Chemistry, 76, 4408–4431 (2011).
408. S. Dutta, N. Bhaduri, R. S. Upadhayaya, N. Rastogi, S. G. Chandel, J. k. Vandavasi, O. Plashkevych, R. A. Kardile, J. Chattopadhyaya. The R-diastereomer of 6′-O-toluoyl-carba-LNA modificationin the core region of siRNA leads to 24-times improved RNAsilencing potency against the HIV-1 compared to its Scounterpart. Med. Chem. Commun., 2 (11) 1110-1119 (2011)
411. Saúl Martínez-Montero, Susana Fernández, Yogesh S.Sanghvi, Jyoti Chattopadhyaya, Muthupandian Ganesan, Namakkal G. Ramesh, Vicente Gotor, and Miguel Ferrero.Design and divergent synthesis of aza-nucleosides from a chiral iminosugar. Journal of Organic Chemistry, 77, 4671-4678 (2012).
412. S. S. Dixit, R. S. Upadhayaya and J. Chattopadhyaya. New Parasite Inhibitors Encompassing Novel Conformationally-locked 5'-Acyl Sulfamoyl Adenosines. Organic & Biomolecular Chemistry, 10 (30), 6121 - 6129 (2012).
415. Q. Li, O. Plashkevych, R.S. Upadhayaya, S.G. Deshpande, A. Földesi, and J. Chattopadhyaya. Diastereomer-Specific Repertoire of 7′R- or 7′S-Me-Carba-Locked Nucleic Acids (cLNAs) in Antisense Oligo/RNA Duplexes and Engineering of Physico-chemical and Enzymological Properties. V.A. Erdmann et al. (eds.), Chemical Biology of Nucleic Acids, RNA Technologies, DOI 10.1007/978-3-642-54452-1_12, © Springer-Verlag Berlin Heidelberg 2014
416. R. S. Upadhayaya, S.S. Dixit, A. Földesi and J. Chattopadhyaya. New Anti-protozoal Agents: Their synthesis and Biological Evaluations. Bioorganic & Medicinal Chemistry Letters, 23, 2750–2758 (2013)