Boris V Nikonenko
Central Institute for Tuberculosis, Russia
Title: Activity of new indole derivatives against Mycobacterium tuberculosis and Mycobacterium avium in HIV combined mycobacteriosis
Biography
Biography: Boris V Nikonenko
Abstract
Given the data of high-level activities of original lead compounds, obtained earlier at All-Union Scientific Research Chemical-Pharmaceutical Institute (does not exist now) and A N Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences (INEOS RAS), we designed now about 300 multi-target compounds in which electron donor (indole and and ferrocene) and electron acceptor pyridine scaffolds, including INH, are linked via N-N-containing pharmacophore groups, either linear or within the heterocyclic structure. Compounds were tested at the Central Institute for Tuberculosis (CNIIT). Results demonstrated that about 40 agents exhibited proven high activity in vitro and ex vivo against both drug-sensitive M. tuberculosis Ð37Rv (MIC = 0.05-2 μg/mL) and the isoniazid (INH)-resistant clinical isolates of M. tuberculosis CN-40 (MIC = 0.018-4.44 μg/mL), as well as against M. avium (MIC = 0.05-1.5 μg/mL for 15 compounds) and other non-tuberculosis HIV co-infections. Thus, these agents were virtually as active as INH against M. tuberculosis H37Rv; however, unlike INH, those showed remarkable activity against the INH-resistant M. tuberculosis strain and M. avium. 3-triazeneindole TU112 demonstrated high level activity against dormant non-culturable M. tuberculosis. In addition, about 80 compounds among the tested ones show MIC values in the range of ≥2 and ≤ 10 μg/mL, thus ~40% of the compounds exhibited appreciable anti-TB activity. The compounds are hybrid molecules designed on a basis of privileged scaffolds – 3-indolyl (substituted at positions 1,2,5) and 2-4-pyridines including isoniazid one. The strategy of designing new agents based on a concept of molecular hybridization, as well as a recently emerging concept of development membrane-active (redox-mediated) agents as a strategy for treating persistent infections.
Recent Publications
1. Nikonenko B, Reddy VM, Bogatcheva E, Protopopova M, Einck L, Nacy CA (2014) Therapeutic efficacy of SQ641-NE against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 58(1): 587-9.
2. Kondratieva T, Azhikina T, Nikonenko B, Kaprelyants A, Apt A (2014) Latent tuberculosis infection: what we know about its genetic control? Tuberculosis (Edinb). 94(5): 462-8.
3. Velezheva V, Brennan P, Ivanov P, Kornienko A, Lyubimov S, Kazarian K, Nikonenko B, Majorov K, Apt A (2016) Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones. Bioorg Med Chem Lett. 26(3): 978-85.
4. Moore JH, van Opstal E, Kolling GL, Shin JH, Bogatcheva E, Nikonenko B, Einck L, Phipps AJ, Guerrant RL, Protopopova M, Warren CA (2016) Treatment of Clostridium difficile infection using SQ641, a capuramycin analogue, increases post-treatment survival and improves clinical measures of disease in a murine model. J Antimicrob Chemother. 71(5): 1300-6.
5. Nikonenko BV, Kornienko A, Majorov K, Ivanov P, Kondratieva T, Korotetskaya M, Apt AS, Salina E, Velezheva V (2016) In vitro activity of 3-triazenoindoles against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother. 60(10):6422-4.