In Vitro Activity of Squaramides and Acyclic Polyamine Derivatives against Trophozoites and Cysts of Acanthamoeba castellanii

Pathogenic strains of Acanthamoeba cause keratitis (AK), granulomatous amoebic encephalitis (GAE), amoebic pneumonitis (AP), and skin infection in human and animals. The treatment of an Acanthamoeba infection is invariably very difficult and not always effective, and compounds that are amebicidic or amebistatic are frequently toxic and/or irritating for humans. Squaramides and polyamine derivatives have been demonstrated to have antitumor and antiprotozoal activity. The aim of this study was to investigate the activity of 5 squaramides and 5 acyclic polyamines against trophozoites and cysts of A. castellanii Neff. Amoebicidal activity against the trophozoites and cytotoxicity against Vero cells were evaluated with a colorimetric assay, using Alamar Blue?, and chlorhexidine digluconate was assayed as the reference drug. The squaramides 3 and 5 and the acyclic polyamine 6 appeared to be the most active against the trophozoites and their cytotoxicity was low, showing selectivity indexes of 28.3, 26, and 25.7, respectively, similar to the control drug, chlorhexidine digluconate (27.6). But only the squaramide 3 showed complete cysticidal activity at the concentrations of 100 and 200 μM, as the chlorhexidine digluconate. Further studies of the mechanism of action and in vivo assays are needed, but squaramide 3 could be used for developing novel therapeutic approaches against Acanthamoeba infections.

Enantioselective Synthesis of N-Phenyl-dihydropyrano[2,3-c]-pyrazoles via Cascade Michael Addition/Thorpe-Ziegler Type Cyclization Catalyzed by a Chiral Squaramide

Enantioselective synthesis of biologically active dihydropyrano[2,3-c]pyrazoles has been achieved through a squaramide-catalysed Michael addition/Thorpe-Ziegler type cyclization cascade reaction between arylidenepyra-zolones and malononitrile.A series of optically active dihydropyano[2,3-c]pyrazoles were obtained in excellent yields(up to 99%)and moderate to good enantioselectivities(up to 79%ee)under mild reaction conditions.

Stereoselective Ring-Opening Polymerization of rac-Lactide Catalyzed by Squaramide Derived Organocatalysts at Room Temperature

Substa ntial progresses have bee n made toward the developme nt of meta I-free catalysts for stereoselective rin g-ope ning polymeriza-tion(ROP)of rac-lactide.Yet the discovery of organic catalysts effective at ambient temperature remains a major challenge.Here,the bifunctional H-bonding catalyst SQ-1 containing a basic tertiary amine and squaramide motif proved to be good candidate for the stereoselective ROP of rac-lactide at room temperature,yielding stereoregular polylactide with controlled molecular weights(up to 21.1 kg/mol)and high tacticity(PjESC up to 0.88).Furthermore,binary H-b on ding catalytic system con sisti ng of squaramides(SQ-2 to SQ-6)and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU)could efficiently promote the ROP of rac-lactide at room temperature within short reaction time.Among them,the most bulky squaramide SQ-2 exhibited the best steroselectivity towards the ROP of rac-lactide without transesterification side reactions during the polymerization process.The resulting polylactides were proved to have controlled molecular weights as high as 22.2 kg/mol and narrow distributions(1.10-1.24).

Heterogeneous catalysts with programmable topologies generated by reticulation of organocatalysts into metal-organic frameworks:The case of squaramide

A well-established strategy to synthesize heterogeneous,metal-organic framework(MOF)catalysts that exhibit nanoconfinement effects,and specific pores with highly-localized catalytic sites,is to use organic linkers containing organocatalytic centers.Here,we report that by combining this linker approach with reticular chemistry,and exploiting three-dimensioanl(3D)MOF-structural data from the Cambridge Structural Database,we have designed four heterogeneous MOF-based catalysts for standard organic transformations.These programmable MOFs are isoreticular versions of pcu IRMOF-16,feu UiO-68 and pillared-pcu SNU-8X,the three most common topologies of MOFs built from the organic linker p.p'-terphenyldicarboxylic acid(tpdc).To synthesize the four squaramide-based MOFs,we designed and synthesized a linker,4,4’-((3,4-dioxocyclobut-1-ene-1,2-diyl)bis(azanedyil))dibenzoic acid(Sq_tpdc),which is identical in directionality and length to tpdc but which contains organocatalytic squaramide centers.Squaramides were chosen because their immobilization into a framework enhances its reactivity and stability while avoiding any self-quenching phenomena.Therefore,the four MOFs share the same organocatalytic squaramide moiety,but confine it within distinct pore environments.We then evaluated these MOFs as heterogeneous H-bonding catalysts in organic transformations:a Friedel-Crafts alkylation and an epoxide ring-opening.Some of them exhibited good performance in both reactions but all showed distinct catalytic profiles that reflect their structural differences.

Highly Enantioselective Intramolecular Morita-Baylis-Hillman Reaction Catalyzed by Mannose-Based Thiourea-phosphine

The saccharide-based chiral bifunctional thiourea-phosphines were developed as chiral organocatalysts for the intramolecular Morita-Baylis-Hillman reaction of o^-formyl-enones. With only 2 tool% of thiourea-phosphine cata- lyst 3c, chiral functionalized cyclohexenes were achieved under mild reaction conditions with excellent yields and enantioselectivities.

A novel squaraine dye with squaramide as a scaffold and the colorimetric detection of amine

A novel unsymmetrical squaramide-linked squaraine dye（SQ） has been synthesized through squaramide 3 and semisquaraine 6. The molecular structure of SQ has been characterized by ~1H NMR,IR and MS.Due to the influence of the hydrogen bond and the solvent effect,SQ exhibits unique spectral properties compared with typical squaraine dyes.For its excellent ability of binding primary amine,SQ is a promising receptor of recognizing primary amine.

Enantioselective Construction of Functionalized Thiochromans via Squaramide-Catalyzed Asymmetric Cascade Sulfa-Michael/Michael Addition

An efficient enantioselective cascade sulfa-Michael/Michael addition reaction of trans-3-(2-mercaptophenyl)-2-propenoic acid ethyl ester with nitroalkenes catalyzed by a chiral squaramide catalyst was disclosed.This cascade reaction afforded thiochroman derivatives with three contiguous stereocenters in high yields(up to 94%),excellent diastereoselectivities(up to>25∶1 dr)and enantioselectivities(up to 99% ee).

Asymmetric Michael addition reactions catalyzed by a novel upper-rim functionalized calix[4]squaramide organocatalyst

A novel upper-rim functionalized calix[4]squaramide organocatalyst bearing bis-squaramide and cyclohexanediamine scaffolds was designed and prepared to catalyse a serial of asymmetric Michael addition of 1,3-dicarbo nyl compounds to a,β-unsaturated carbonyl compounds in high yields(up to 99%)and good to excellent enantiomeric excesses(up to 99%ee).The comparative experiments indicated that the cooperative effect between calixarenes cavitives and chiral catalytic centers on this calix[4]squaramide catalyst could promote these reactions.Moreover,this strategy also provides valuable and easy access to chiral chromene,naphthoquinone and acetylacetone derivatives,which are important skeletons in biological and pharmaceutical compounds.

Enantioselective chlorination of β-keto esters and amides catalyzed by chiral copper(Ⅱ) complexes of squaramide-linked bisoxazoline ligand

Enantioselective chlorination of b-keto esters and amides catalyzed by squaramide-linked bisoxazoline ligand–Cu（OAc）2complexes was investigated. The corresponding chlorinated products were obtained in excellent yields with moderate enantioselectivities. The effect of solvent, temperature, Lewis acid, and ligand structure on the reaction is discussed. This was the first investigation of catalytic asymmetric achlorination of b-keto amides. This study has highlighted that a simple chiral squaramide–oxazoline with cheap Cu（OAc）2 H2 O complexes can catalyze this chlorination.