Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds

Access to β‐Ketonitriles through Nickel‐Catalyzed Carbonylative Coupling of α‐Bromonitriles with Alkylzinc Reagents

“…β‐Ketonitriles serve as useful reactive precursors in organic synthesis . Due to the relative position of the ketone and nitrile functionalities, this class of organic compounds has been exploited for the synthesis of numerous heterocycles, including isoxazoles, pyrazoles, pyrimidines, pyrans, and thiazolidines, representing important structural fragments of biologically active molecules. Furthermore, the enantioselective reduction of β‐ketonitriles yields β‐hydroxynitriles that are common intermediates for the preparation of various pharmaceuticals, for example, the antiparasitic agent, levamisole …”

“…[1] Due to the relative position of the ketonea nd nitrile functionalities, this class of organic compoundsh as been exploited for the synthesis of numerous heterocycles, including isoxazoles, [2] pyrazoles, [3] pyrimidines, [4,5] pyrans, [6] and thiazolidines, [7] representing important structuralf ragments of biologically active molecules. [1] Due to the relative position of the ketonea nd nitrile functionalities, this class of organic compoundsh as been exploited for the synthesis of numerous heterocycles, including isoxazoles, [2] pyrazoles, [3] pyrimidines, [4,5] pyrans, [6] and thiazolidines, [7] representing important structuralf ragments of biologically active molecules.…”

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

“…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 ) …”

Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases

“…Compounds 7c and 7o are distinctly acetazolamide-like. The difficult-to-inhibit hCA IV is not giving high inhibition results throughout, considering the "detrimental methoxy" phenomenon present in 7g-7l (previously noted by us 10 and tentatively justified). When it comes to hCA IV isoform, some striking restoration of potency is observed in 7b (on top of a high selectivity) and, particularly, in 7n (where overall selectivity is not that good).…”

“…The substrates are relevant to, among other pharmacologically sound molecules, known blockbuster antipyretic Celebrex as well as tricyclic congeners 3a-e earlier reported by Marini ( Figure 3) 8 . Moreover, through some less systematic approach, the direct sulfochlorination of (hetero)aromatics has very recently given rise to: (i) 5-thienyl-1,3-oxazolecarboxamides 4 (where a remarkable potency toward hCA II with K i ¼ 0.01 nM was achieved) 9 and (ii) a series of isoxazole bis-sulfonamides, exemplified by 5 clearly offering an alternative ZBG binging mode and a remarkable K i of 9.4 nM against hCA IV, an extremely rare hCA to target with such a potency and selectivity (Figure 4) 10 . These isolated and nonetheless successful results, prompt us to undertake a direct sulfochlorination approach to produce compounds which would not only provide a wealthy entry into the realm of CAI but also provide the reader with an easy-to-read compendium of methods on direct shofochlorination of Celebrexlike N-arylpyrazoles.…”