Medicinal chemistry in an academic environment: removing “chemical blind spots”
The task of doing good MedChem in an academic environment has been the subject of two recent comments which provide excellent illustrations of the issues involved in such endeavor (1,2). In the last decade, we have attempted to address some of these issues by providing our modest expertise in the domain and we also oriented our research in organic chemistry toward removing “chemical blind spots” existing in the chemical space of drug-like compounds. Our most advanced project was based on the observation that if there is a great number of pyrazole-5(2H)-ones described in the literature and patents (resulting from the use of the Knorr reaction), there are much less examples of pyrazole-3(2H)-one derivatives. From a simple process to prepare alkoxypyrazoles (3) we set to lessen this difference and prepared quite a few libraries of new chemical entities (4-13). So far, out of this ground work, an antiviral screening campaign, made on the CBC platform at the Institut Pasteur, led to an original series of strong inhibitors of human dihydroorotate dehydrogenase (14) which are illustrated by compounds 1 and 2 (15,16).
We are also working on the design of original bacterial type IIA topoisomerases via rescaffolding strategies. The last two decades have seen very important efforts, made by the pharmaceutical industry (17), to discover new antibacterials. If many news series of strong inhibitors of type IIA topoisomerases have been reported (18), they are yet to be used as antibacterials (19). From the wealth of structural data describing the binding modes of these inhibitors to bacterial type IIA topoisomerases (18), we are trying to design and synthesize original series which may overcome some of the problems encountered while trying to develop these compounds into actual antibiotics.
Finally, we became aware of the deep sea bioluminescent creatures luciferins such as coelenterazine or “varguline” (the luciferin of Vargula hilgendorfii) as well as many artificial analogues which found extensive uses in biology, including high-throughput screenings.
Interestingly, if an array of synthetic pathways to prepare such imidazopyrazines have been reported (20), we believe that, as for pyrazole chemistry, a chemical blind spot is existing in pyrazine chemistry. We should be reporting in the future in a project aiming at lifting this and, as for the alkoxypyrazoles, we hope that amongst the original compounds made in the course of this work some will turn out to display biological effects of interest in the screening campaigns made at the Institut Pasteur.
Thank you for reading
Yves L Janin
(1) Baell, J.; Walters, M. A. Chemical con artists foil drug discovery. Nature 2014, 513, 481-483.
(2) Baell, J. B. Screening-Based Translation of Public Research Encounters Painful Problems. ACS Med. Chem. Lett. 2015, 6, 229-234.
(3) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. An improved preparation of 3-alkoxypyrazoles. Synthesis 2008, 3504-3508.
(4) Coutant, E. P.; Janin, Y. L. A study of Negishi cross-coupling reactions with benzylzinc halides to prepare original 3-ethoxypyrazoles. Synthesis 2015, 47, 511-516.
(5) Ermolenko, M. S.; Guillou, S.; Janin, Y. L. Pyrazole-3/5-carboxylic acids from 3/5-trifluoromethyl NH-pyrazoles. Tetrahedron 2013, 69, 257-263.
(6) Janin, Y. L. Preparation and chemistry of 3/5-halogenopyrazoles. Chem. Rev. 2012, 112, 3924-3958.
(7) Salanouve, E.; Retailleau, P.; Janin, Y. L. Few unexpected results from a Suzuki-Miyaura reaction. Tetrahedron 2012, 68, 2135-2140.
(8) Salanouve, E.; Guillou, S.; Bizouarne, M.; Bonhomme, F. J.; Janin, Y. L. 3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results. Tetrahedron 2012, 68, 3165-3171.
(9) Guillou, S.; Bonhomme, F. J.; Ermolenko, M. S.; Janin, Y. L. Simple preparations of 4 and 5-iodinated pyrazoles as useful building blocks. Tetrahedron 2011, 67, 8451-8457.
(10) Guillou, S.; Janin, Y. L. 5-Iodo-3-ethoxypyrazoles, an entry point to new chemical entities. Chem. Eur. J. 2010, 16, 4669-4677.
(11) Guillou, S.; Bonhomme, F. J.; Chahine, D.; Nesme, O.; Janin, Y. L. N-arylation of 3-alkoxypyrazoles, the case of the pyridines. Tetrahedron 2010, 66, 2654-2663.
(12) Guillou, S.; Nesme, O.; Ermolenko, M. S.; Janin, Y. L. Carbon-4 arylation of 3-alkoxypyrazoles. Tetrahedron 2009, 65, 3529-3535.
(13) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Nitrogen’s reactivity of various 3-alkoxypyrazoles. Tetrahedron 2009, 65, 2660-2668.
(14) Munier-Lehmann, H.; Vidalain, P.-O.; Tangy, F.; Janin, Y. L. On dihydroorotate dehydrogenases, their inhibitors and uses. J. Med. Chem. 2013, 56, 3148-3167.
(15) Munier-Lehmann, H.; Lucas-Hourani, M.; Guillou, S.; Helynck, O.; Zanghi, G.; Noel, A.; Tangy, F.; Vidalain, P. O.; Janin, Y. L. Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). J. Med. Chem. 2015, 58, 860-877.
(16) Lucas-Hourani, M.; Munier-Lehmann, H.; El Mazouni, F.; Malmquist, N. A.; Harpon, J.; Coutant, E. P.; Guillou, S.; Helynck, O.; Noel, A.; Scherf, A.; Phillips, M. A.; Tangy, F.; Vidalain, P. O.; Janin, Y. L. Original 2-(3-alkoxy-1H-pyrazol-1-yl)azines inhibitors of human dihydroorotate dehydrogenase (DHODH). J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00606.
(17) Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nature Rev. 2007, 6, 29-40.
(18) Mayer, C.; Janin, Y. L. Non quinolone inhibitors of bacterial type IIA topoisomerases, a feat of bioisosterism. Chem. Rev. 2014, 114, 2313-2342.
(19) Bisacchi, G. S.; Manchester, J. I. A New-Class Antibacterial-Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. ACS Infect. Dis. 2015, 1, 4-41.
(20) Coutant, E. P.; Janin, Y. L. Synthetic accesses to coelenterazine and other imidazo[1,2-a]pyrazine-3-one luciferins, essential tools for bioluminescence-based investigations. 2015, Chem. Eur. J. doi:10.1002/chem.201501531.