|Medicinal Chemistry |
|B.S., Chemistry (Organic Chemistry), 1992, National University of Córdoba, Córdoba, Argentina, 1992. |
|Ph.D., Chemistry, 1999, National University of Córdoba, Córdoba, Argentina |
|Postdoctoral, 2000-20002, The University of Mississippi |
Research: Medicinal ChemistryI. Opioid Analgesics.
Opioid analgesics have remained the mainstay in the management of severe pain. They produce their effect through interaction with , or receptors in the central nervous system or in the peripheria. Centrally acting opioids (morphine) are potent analgesics and are the most widely used. However, it has been reported a number of side effects (i.e., tolerance, dependence, respiratory depression, and inhibition of gastrointestinal transit) that often limit their use. Centrally acting opioid agonists have also been shown to be potent analgesics but their therapeutic utility is limited because they can elicit dysphoria and other adverse effects. A great deal of attention is pay to the research and development of opioids with novel activity profiles or with distinct physico-chemical properties due to the limitation of the analgesics that are in use.
Continuing advances in understanding the pharmacology of pain and analgesia that have resulted from the application of molecular biology techniques and the development of selective ligands for the various receptor classes involved in nociceptive transmission, have established that pain is an extremely complex and dynamic process involving multiple interrelated neurotransmitter/neuromodulator systems in the spinal cord, in ascending and descending spinal pathways, and at supraspinal sites.
The identification of novel compounds that more effectively treat both acute and chronic pain states, and which lack side effects associated with current therapies, remains a major challenge in biomedical and pharmaceutical research.
My research interests are focused in the design and synthesis of ligands to investigate the opioid receptors. Using the experience gained in the last years is my interest to use natural products that may have affinities with the opioid receptors as scaffolds in the design of small molecules or semi-synthetic analogues.
II. Antiinfective agents.
The well-known state of AIDS disease, caused by the infection of the human immunodeficiency virus, is estimated in over 40 million cases worldwide. This disease results in a severely immuno compromised state leading to infections by other diseases such as tuberculosis, ultimately, enhancing the dissemination of other opportunistic diseases such as cytomegalovirus. Toxoplasmosis is a disease prominent in aids patients, but infection is also a concern in pregnant women (congenital toxoplasmosis) and is spread by a household cat. Cytomegalovirus (beta-herpesvirus) is an opportunistic infection disseminated in individuals with compromised immune function. Approximately half of the adult population in developed countries has been infected with HCMV (human cytomegalovirus).
HCMV protease inhibitors. HCMV protease is a protease produced by the virus as an essential capsid assembly protein. A great deal of attention is being paid to these enzymes as a therapeutic targets for the development of novel antiherpetic. A variety of drugs have been developed to treat herpes virus infection, including naturally occurring proteins and synthetic nucleoside analogs. The drugs currently used to treat HCMV infection, such as ganciclovir (GCV), cidofovir (CDV), foscarnet (PFA), an valganciclovir, an orally bioavailable valine ester prodrug of ganciclovir, lack the acceptable side efect and safety profiles of the drugs approved for treatment of other herpes viruses.
Antituberculosis agents. Tuberculosis (TB) is a chronic infectious disease caused by mycobacteria of the “tuberculosis complex”, including Mycobacterium bovis, Mycobacterium africanum and mainly Mycobacterium tuberculosis. TB is the classic example of a disease caused by an intracellular parasite. The infection is usually transmitted from person to person by the inhalation of infective droplet nuclei that result from the aerosolization of respiratory secretions and may involve any organ system, but the lung is the usual site of the primary lesion and the main organ infected. According to World Health Organization (WHO), TB kills more youth and adults than any other infectious disease in the world today. It is a worse killer than malaria and AIDS combined and kills more women than all the causes of maternal mortality. It is responsible for 100,000 children deaths each year.
Patent and Patent Applications:
“Preparation of New Antimicrobial Benzenesulfonamidefluorquinolones”. M. Nieto, F. Alovero, M. Mazzieri y R. Manzo. Argentinean Patent Application # P970100693. (1997)
1. B. E. Kane, M. J. Nieto, C. R. McCurdy, D. M. Ferguson. A unique binding epitope for salvinorin A, a non-nitrogenous kappa-opioid receptor agonist. FEBS J. (2006) 273, 1966-74.
2. M. J. Nieto, F. L. Alovero, R. H. Manzo, M. R. Mazzieri. Benzenecarboxamide Analogues of Fluoroquinolones (BCFQs). Antibacterial Activity and SAR Studies. Lett. Drug Design and Discovery (2006) 3(2), 108-111.
3. C. R. McCurdy, K. J. Sufka, J.E. Warnick, M.J. Nieto. Analgesic Profile of Salvinorin A, a Structurally Unique Kappa Opioid Agonist. Pharmacol, Biochem and Behavior, (2006) 83, 109-113.
4. M. Nieto, F. Alovero, R. Manzo and M. Mazzieri. "A New Class Of Fluoroquinolone: Benzenesulfonamidefluoroquinolones (BSFQs). Antibacterial Activity And SAR Studies. II." Eur. J. Med. Chem. (2005) 40(4), 361-369.
5. M.J. Nieto, A.E. Phillip, J. Poupaert, C.R. McCurdy. “Solution-Phase Parallel Synthesis of Spirohydantoins Derivatives” J. Comb. Chem. (2005) 7(2), 258-263.
6. E. Muri, M. J. Nieto, J. Williamson. "Hydroxamic Acids as Pharmacological agents. An Update". Med. Chem. Rev. On Line (2004) 1(4) 385-394.
7. M. Nieto, P.Rodríguez-Manzanares, R. Manzo, M. Mazzieri. “Hydrophobicity estimations of benzenesulfonamidofluoroquinolones (BSFQs) by RP-LC. Influence of chromatographic parameters in QSAR studies”, Med.Chem.Res. (2003) 12(2), 94-110.
8. B. Bradbury, P. Bartyzel, T. S. Kaufman, M. J. Nieto, S. Scesney, B. Gaumond, H. C. Marsh, Jr., R. D. Sindelar. “Synthesis and Complement Inhibitory Activity of B/C/D-Ring Analogues of the Fungal Metabolite 6,7-Diformyl-3’,4’,4a’,5’,6’,7’,8’,8a’-octahydro-4,6’,7’-trihydroxy-2’,5’,5’,8a’-tetramethylspiro [1’(2’H)-naphthalene-2(3H)-benzofuran]”. J. Med. Chem. (2003) 46, 2697-2705.