Towards discovery of effective urease inhibitors; we disclose here a hybrid series of imidazole and pyrazole motifs as potent antiurease agents. A para-toluenesulfonic acid (TsOH) catalyzed, facile synthetic approach was employed for the preparation of targeted molecular designs in good yields upto 94 %. The novel scaffolds were characterized by different spectroscopic means (FTIR, NMR, and Mass spectrometry) and elemental analysis helped to identify the purity of these compounds. Afterwards, the derivatives was tested against Jack bean's urease enzyme to explore their inhibiting potencies. All analogues (4 a-4 l) were found active against the studied enzyme in comparison with the standard drug thiourea (IC 50 = 21.26 � 0.12 μM). However, following dibromo substituted derivatives: 4 f, 4 g, 4 h, 4 i, 4 j, 4 k, and 4 l were surfaced out as potent urease inhibitors among the series. The identified lead candidates were meta-nitro substituted 4 k with IC 50 = 0.7 � 0.002 μM and a para-nitro containing compound 4 l with IC 50 = 1.0 � 0.003 μM. As observed in docking calculations, ionic and hydrogen bonding, π-stacking, interaction with nickel ions and other hydrophobic interactions probably stabilized the ligand bindings at the active site of urease.
of Aberdeen. Scotland AB9 2UECyclisations of 2'-amino-, 2'-acetylamino-. or 2'-methylamino-2-methoxybenzophsnones occur in thz presence of sodium hydride in dimethyl sulphoxide to give acridone alkaloids. This cyclisation has relevance to the biosynthesis of these alkaloids. An alternative cyclisation can occur, giving 4-arylquinolines or 4-arylquinolones.THE acridone alkaloids compiise ca. 35 members pro-mild reduction of 2,4,6-trihydroxy-2'-nitrobenzophenone duced only by the Rutaceae family of higher plants. (5) with zinc dust in ethanol to give solely 1,3-dihydroxy-Their mode of biosynthesis was postulated by Sir Robert 9-acridone (4), presumably via the 2-aminobenzo-R~b i n s o n ,~ who suggested that anthranilic acid con-phenone (6), the keto tautomer (7) of which could underdensed with acetic acid to give the tricyclic acridone go a Schiff's base type condensation.* Methylation of system.one or more of the hydroxy-functions in (5) prevented the early observation that 2-aminobenzaldehyde (1) cyclisation concomitant with reduction. Cyclisation condensed easily with phloroglucinol (2) t o give 1,3-of 2-methoxyaminoor 2-methoxyacetamido-benzodihydroxyacridine (3). Compound (3) can be con-phenones can be achieved at room temperature through verted through oxidation into 1,3-dihydroxy-9-acridone the use of sodium hydride in dimethyl sulphoxide (4) (Scheme 1).whereby 2'-acetamido-2-methoxybenzophenone and related compounds yield g-acridone~.~ Application of this This postulate may have been prompted byIn modern terms this sequence could involve the I reaction of an activated anthranilic acid (as its co-type of cyclisation has now enabled the synthesis of a enzyme) with a triketide to produce an aminobenzo-number of acridone alkaloids. phenone which on cyclisation produces a dihydroxy-Thamnosma montana lo, If. contains both acridone (8 ;9-acridone. In support of this hypothesis, both an-R1 = R2 = R3 = H) and its 10-methyl derivative (8;thranilic and N-methylanthranilic acid have been shown R1 = R2 = H, R3 = Me); the synthesis of acridone experimentally t o be precursors of the acridone alkaloids from 2'-amino-2-niethoxybenzophenone proceeds in 47% in Acronychia baueri and in Glycosmis arborea,' and the yield.g FOI N-methyl-9-acridone (8; R1 = R2 = H, cyclisation step has been achieved quantitatively by Stirling, December 17th, 1974. R.A. Watt, Chem. and Ind., 1,975, 744.
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