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As part of our ongoing antileishmanial structure–activity relationship study, a structural simplification of the 3‐nitroimidazo[1,2‐a]pyridine ring to a 5-nitroimidazole moiety was conducted. A series of novel 2,4-disubsituted 5-nitroimidazole derivatives, including the 5-nitroimidazole analog of Hit A and the 4-phenylsulfonylmethyl analog of fexinidazole, were obtained by using the vicarious nucleophilic substitution of hydrogen (VNS) reaction, to substitute position 4, and by using the tetrakis(dimethylamino)ethylene methodology to modulate position 2. The molecular structures of eight novel 5-nitroimidazoles were characterized by 1H NMR, 13C NMR, LC/MS, and HRMS. The in vitro antileishmanial activity of these compounds was evaluated against the promastigote form of Leishmania infantum and their influence on cell viability was assessed on the human hepatocyte HepG2 cell line. The 4-phenylsulfonylmethyl analog of fexinidazole showed the best selectivity index of the series, displaying good activity against both the promastigote form of L. infantum (EC50 = 0.8 µM, SI > 78.1) and the promastigote form of Leishmania donovani (EC50 = 4.6 µM, SI > 13.6), and exhibiting low cytotoxicity on the HepG2 cell line (CC50 > 62.5 µM).

In continuation of our research program to develop original synthetic methods using TDAE methodology on nitroheterocyclic substrates, we were able to generate for the first time a stable carbanion in position 2 of the 5-nitroimidazole scaffold. Starting from a 2-chloromethyl-4-phenylsulfonylmethyl-5-nitroimidazole intermediate, prepared by the vicarious nucleophilic substitution of hydrogen (VNS) reaction, we selectively introduced a N-tosylbenzylimine moiety at position 2 without reducing the sulfone at position 4, leading to the formation of N-[1-(2-chlorophenyl)-2-{1-methyl-5-nitro-4-[(phenylsulfonyl)methyl]-1H-imidazol-2-yl}ethyl]-4-methylbenzenesulfonamide in 47% yield. This new synthetic method using TDAE should allow access to new 2-substituted 5-nitroimidazole derivatives with various electrophiles such as carbonyls and other N-tosylbenzylimines. [ABSTRACT FROM AUTHOR]

3-, 5-, 6-, 7- and 8-Nitroquinolines react with 4-amino-1,2,4-triazole in basic medium (potassium tert-butoxide-dimethyl sulfoxide) giving amino products of the vicarious nucleophilic substitution (VNS) of hydrogen, predominantly at ortho position to the nitro group, except 8-nitroquinoline, which reacts at para position. Additionally, furazano[3,4-f]- and furazano[3,4-h]quinoline were obtained in the case of 5- and 8- nitroquinoline, respectively. 2-Nitroquinoline was aminated to 2-quinolino(1,2,4-triazol-4-yl)amine in these conditions. [ABSTRACT FROM AUTHOR]

Carbanions of chloromethyl 4-tolylsulfone, bromo- and chloromethanesulfomorpholide, and neopentyl chloromethanesulfonate react with benzonaphthyridines and their N-oxides via two pathways: vicarious nucleophilic substitution of hydrogen and annelation. The results are rationalized in terms of the negative charge delocalization in the intermediate σ-adducts. [ABSTRACT FROM AUTHOR]

Treatment of benzonaphthyridines with chloromethyl phenyl sulfone in the presence of base led to the formation of aziridine rings annelated to the benzonaphthyridine skeleton, whereas their N-oxides underwent vicarious nucleophilic substitution of hydrogen (VNS), thus leading to the corresponding phenylsulfonylmethyl derivatives. [ABSTRACT FROM AUTHOR]