Zafer Cesur

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

ABSTRACT A new class of N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide inhibitors of influenza virus hemagglutinin (HA)-mediated membrane fusion that has a narrow and defined structure-activity relationship was identified. In Madin-Darby canine kidney (MDCK) cells infected with different strains of human influenza virus A/H3N2, the lead compound, 4c, displayed a 50% effective concentration of 3 to 23 μM and an antiviral selectivity index of 10. No activity was observed for A/H1N1, A/H5N1, A/H7N2, and B viruses. The activity of 4c was reduced considerably when added 30 min or later postinfection, indicating that 4c inhibits an early step in virus replication. 4c and its congeners inhibited influenza A/H3N2 virus-induced erythrocyte hemolysis at low pH. 4c-resistant virus mutants, selected in MDCK cells, contained either a single D112N change in the HA2 subunit of the viral HA or a combination of three substitutions, i.e., R220S (in HA1) and E57K (in HA2) and an A-T substitution at position 43 or 96 of HA2. The mutants showed efficiency for receptor binding and replication similar to that of wild-type virus yet displayed an increased pH of erythrocyte hemolysis. In polykaryon assays with cells expressing single-mutant HA proteins, the E57K, A96T, and D112N mutations resulted in 4c resistance, and the HA proteins containing R220S, A96T, and D112N mutations displayed an increased fusion pH. Molecular modeling identified a binding cavity for 4c involving arginine-54 and glutamic acid-57 in the HA2 subunit. Our studies with the new fusion inhibitor 4c confirm the importance of this HA region in the development of influenza virus fusion inhibitors.

Fused heterocycles: synthesis of some new imidazo[1,2-a]- pyridine derivatives.

Some new thiazolidines and spirothiazolidines derived from hydrazones of 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid hydrazide, a bioisosteric derivative of isoniazid, were synthesized and characterized by analytical, IR, (1)H- and (13)C-NMR and mass spectral data. Some of the newly synthesized compounds were screened for their antimycobacterial activities. None of the tested compounds showed significant in vitro antituberculous activity at 6.25 mirog/mL (MIC rifampin 0.031 microg/mL).

Microwave assisted synthesis and anti-influenza virus activity of 1-adamantyl substituted N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives.

A microwave-assisted three-component one-pot cyclocondensation method was applied for the synthesis of novel N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide compounds carrying an adamantyl moiety. The structures of the compounds were confirmed by spectral and elemental analysis. All compounds were evaluated for antiviral activity against influenza A (H1N1 and H3N2) and influenza B virus in MDCK cell cultures. The compounds displayed a confined structure-activity relationship. The N-(2,8-dimethyl-3-oxo-1-thia-4-azaspiro[4.5]dec-4-yl)adamantane-1-carboxamide 3b was the most potent inhibitor [antiviral EC(50): 1.4 μM against influenza A/H3N2 virus]. Its strong inhibitory effect in a virus hemolysis assay supports that 3b acts as an influenza virus fusion inhibitor by preventing the conformational change of the influenza virus hemagglutinin at low pH.

FUSED HETEROCYCLES : SYNTHESIS OF SOME NEW IMIDAZOTHIAZOLES

Reaction of aldehyde-hydrazones or semicarbazones bearing an imidazo [2, 1-b] [1,3]thiazole ring system with mercaptoalkanoic acids were investigated. Antimycobacterial activities of compounds thus obtained were evaluated against Mycobacterium tuberculosis H37RV using rifampine as standard. Treatment of tuberculosis is still one of the major problems due to the rise of multidrug resistant tuberculosis in clinical practice. Since many years, isonicotinic acid hydrazide (isoniazide) has been used as a principal drug for the treatment of the desease. The effects of substituents and bioisosteric replacements on its antituberculous activity are still under investigation (1). This prompted us to synthesize 6-methylimidazo [2, l-£>] [1, 3] thiazole-5-carbohydrazide 2, a structural analog of isoniazide, and its hitherto unreported derivatives to screen their antituberculous properties. Ar: a,QH5; b,C,;H4F(4); C,QH4C1(4); d, QH4Br (4) ; e, QH4CH3 (4 ) ; f ,QH4OCH3(4) ; g,QH4N02(2) 6-Methylimidazo[2,1-b][l,3]thiazole-5-carbohydrazide was synthesized by the reaction of hydrazine with ethyl 6-methylimidazo [2 , l-£>] [1, 3] thiazole-5-carboxylate (2). 2 reacted with aromatic aldehydes to afford hydrazide-hydrazones 3 which furnished N-(2-aryl-

Synthesis and Structure-Activity Relationship of N-(3-Oxo-1-Thia-4-Azaspiro[4.5]Decan-4-Yl)Carboxamide Inhibitors of Influenza Virus Hemagglutinin Mediated Fusion

GRAPHICAL ABSTRACT Abstract We report on synthesis and the structure-activity relationship of carboxamide-derived inhibitors of the influenza virus fusion function of the viral hemagglutinin. The newly synthesized carboxamides have a backbone structure similar to reported fusion inhibitors, consisting of an aromatic ring system linked to a non-aromatic cyclic system via an amide bridge. Condensation of 2-hydroxybenzohydrazide, 5-chloro-2-hydroxybenzohydrazide or 3-hydroxynaphthalene-2-carbohydrazide, appropriate carbonyl compounds and sulfanyl acids yielded corresponding N-(3- oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamides, using a one-pot three-component cyclocondensation method. The compounds were characterized by IR, 1H-NMR,13C-NMR, and elemental analysis. All compounds were evaluated for antiviral activity against influenza A (H1N1, H3N2) and influenza B viruses in MDCK cell cultures. The contributions of different substituents on the antiinfluenza effect were discussed.