Synthesis of isoxazole-containing sulfonamides with potent carbonic anhydrase II and VII inhibitory properties

Discovery of New Sulfonamide Carbonic Anhydrase IX Inhibitors Incorporating Nitrogenous Bases

“…24 The following structure−activity relationships (SARs) were obtained from the inhibition data reported in Table 1: (i) The inhibitory profile of the screened derivatives against the four CA isoforms was dependent on the length and positioning of the spacer at the benzenesulfonamide scaffold more than on the nature of both the spacer and the nitrogenous base. In this context, the para-substitution at the benzenesulfonamide scaffold was more favorable than meta (3,7,11,15,22, and 26) in inducing effective CA inhibitory properties. Moreover, in the case of the amidic linker at position 4, a direct or two carbon spacer between the amide and the benzene ring led to better inhibitory profiles over a single carbon atom connection in the uracil derivatives (4 and 6) and to a lesser extent for adenines (23, 25, 27, and 29).…”

Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

“…Reported protocols for the reaction of halogenoximes and active methylene nitriles vary significantly in conditions, particularly with respect to the choice of base, which has included Et 3 N,, NaOH, MeONa, EtONa,, , lithium diisopropylamide (LDA), and t BuLi, For our purposes, we initially chose active methylene nitriles 5a – 5h (available from commercial sources) and chloroximes 6a – 6e [preparation previously reported by our group; ( S ) and ( R ) isomers were used to prepare chiral compounds 6b and 6c ] as our model substrates (Figure ). We focused on the use of less nucleophilic bases to extend the possible scope of the reaction.…”

“…The known methods for the construction of the 5‐aminoisoxazole system can be categorized into three general strategies, that is, intramolecular cyclizations [e.g., base‐promoted cyclizations of β‐nitronitriles 1 or the recyclization of cyclopropanes 2 by treatment with PCl 5 or Tf 2 O (Tf = trifluoromethanesulfonyl), Scheme , pathway A ], [4+1] approaches (e.g., reactions of α‐halogenoximes with isonitriles, Scheme , pathway B ;, reactions of 2‐nitro‐1,3‐diarylprop‐2‐en‐1‐ones 3 or N , N ‐bis(silyloxy)enamines 4 with a cyanide source, Scheme , pathway C ; and reactions of ynamides with an azide, Scheme , pathway D ), and [3+2] approaches (Scheme , pathways E and F ). The latter strategy is by far the most widely used and includes the reactions of α‐ketonitriles, malononitriles,, or α,β‐unsaturated nitriles that have a leaving group at the β‐position with NH 2 OH (CCC + NO, Scheme , pathway E ) as well as reactions of halogenoximes with N ‐protected ynamides, or active methylene nitriles (CC + CNO, Scheme , pathway F ) …”

The synthetic and therapeutic expedition of isoxazole and its analogs

“…25) displayed the approximately same anxiolytic activity as that of diazepam at the non-sedative dose. Altug et al (2017) synthesized a series of sulfonamide based 5-amino isoxazole derivatives (128; Fig. 25) and screened for their CA inhibitory properties against four human isoforms: hCA I, hCA II, hCA IV, and hCA VII.…”