Trypanocidal Structure-Activity Relationshipfor Cis- and Trans-methylpluviatolide

Structure activity relationships in the muscarine and the quaternary 1,3-dioxolane (Fourneau series) series are briefly discussed. The most active member of the latter series (2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide, (IX), F2268) was shown to consist of a mixture of 60% cis and 40% trans isomers. The same was found to apply to all synthetic intermediates in that series. Unequivocal assignments of configuration were made by relating various intermediates leading to (IX) and its analogs to D-cis-1,3-dimethyl-1,3-dioxolane itself, obtained by degradation of 1,6-anhydrogalactose. Attempted separation of cis–trans isomers in the 1,3-dioxolane series was not successful. However, a mixture of cis, trans-2-trichloromethyl-4-hydroxymethyl-1,3-dioxolane (XVI) could be fractionated by crystallization of the corresponding tosylates. Catalytic hydrogenolysis converted the pure cis- and trans-trichloromethyl derivatives (XVII) and (XVIII) to pure cis- and trans-2-methyl-4-hydroxymethyl-1,3-dioxolane tosylates (XIX) and (XX), which eventually afforded for the first time pure cis-F2268 and trans-F2268 (XXII) and (XXIII).Optically active members in the 1,3-dioxolane series were prepared. Members of the D(−)-series were conveniently obtained from D-isopropylidene glycerol. Members of the L(+)-series could be obtained in optically impure forms by resolution of dl-tertiary bases such as (XXXVI) with D- and L-dibenzoyltartaric acid. The best preparations had an optical purity not exceeding 32%. The resolution of the cis base (X) was unsuccessful.The synthesis of an oxazoline analog, (XLIV), of F2268 was accomplished. The reaction sequence involves solvolysis of N-acetyl-2,3-dibromo-n-propylamine (XLI) to give the 5-bromomethyl-2-methyloxazoline (XLII). This unstable intermediate was reacted with dimethylamine to give the tertiary base (XLIII), which was quaternized with methyl iodide whereupon the quaternary base (XLIV) was formed in good yield. The structure of the latter was established by an independent synthesis of the hydrolysis product (XLV).Preliminary pharmacological data are reported for the various new quaternary salts. The compounds were assayed for cholinomimetic activity. It is concluded from these studies that quaternary 1,3-dioxolanes display structure-activity relationships analogous to the muscarones. The use of triethylammonium analogs has revealed a large degree of preference of cholinergic receptors for the presence of a cis configuration in 2,4-disubstituted-1,3-dioxolanes. It was also noted that the oxazoline derivative (XLIV) ranks amongst the most active cholinomimetics thus far reported. Relationships between configuration and activity are briefly discussed.

Download Full-text

Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

10.33774/chemrxiv-2021-0b2wc-v2 ◽

2021 ◽

Author(s):

Khyati Gohil ◽

M. Zain Kazmi ◽

Florence Williams

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Signaling Proteins ◽

Neurotrophic Activity ◽

Structure Activity ◽

Cyclohexene Ring ◽

Pharmacokinetic Properties ◽

Pkc Inhibitors ◽

Cis And Trans ◽

Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

Download Full-text

Preparation of Racemic cis- and trans-2-(2-Alkoxyphenylcarbamoyloxy)cycloheptylmethylpiperidinium Chlorides

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19940675 ◽

1994 ◽

Vol 59 (3) ◽

pp. 675-682 ◽

Cited By ~ 2

Author(s):

Fridrich Gregáň ◽

Viktor Kettmann ◽

Pavol Novomeský ◽

Július Sivý

Keyword(s):

Fractional Crystallization ◽

Local Anesthetics ◽

Conformationally Constrained ◽

Structure Activity Relationships ◽

Structure Activity ◽

Cis And Trans

The synthesis of two pairs of the title diastereomers, which represent conformationally constrained analogues of the phenylcarbamate local anesthetics, is described. The synthesis was accomplished by starting from cycloheptanone and 2-alkoxyanilines and the intermediate diastereomers of 2-aminomethylcycloalkanols (VI, VII) were separated as their 4-nitrobenzoyl derivatives (IV, V) by extraction and fractional crystallization. The prepared compounds (VIIIa, VIIIb, IXa, and IXb) are assumed to be of help in interpreting the structure activity relationships within this class of drugs.

Download Full-text

The synthesis and preliminary pharmacological evaluation of racemic cis and trans 3-alkylfentanyl analogues

Journal of the Serbian Chemical Society ◽

10.2298/jsc0407511i ◽

2004 ◽

Vol 69 (7) ◽

pp. 511-526 ◽

Cited By ~ 9

Author(s):

Milovan Ivanovic ◽

I.V. Micovic ◽

Sonja Vuckovic ◽

Milica Prostran ◽

Zoran Todorovic ◽

...

Keyword(s):

Alkyl Halides ◽

The Novel ◽

Subsequent Reduction ◽

Mild Acid Hydrolysis ◽

Step Method ◽

Structure Activity ◽

Quantitative Separation ◽

Propionyl Chloride ◽

Cis And Trans ◽

Mild Acid

A general, five step method for the synthesis of 3-alkylfentanyl analogues (i.e., cis and trans 3-alkyl-4-anilidopiperidines 6.1?6.6) has been developed. The starting N-phenethyl- 4-piperidone 1 was first converted into the cyclohexylimine derivative 2, ?-deprotonated with butyllithium and the resulting imine anion efficiently monoalkylated with primary and secondary alkyl halides. After mild acid hydrolysis, the obtained 3-alkyl-4-piperidones 3.1?3.6 were isolated in good yields (79?85 %), then condensed with aniline to form imines 4.1?4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1?5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1?5.6 (29?51 % yield) and trans 5.1?5.6 (19?27%yield) with the cis/trans ratio in the range 7/3?6/4. The synthesiswas concluded by N-acylation of the purified 5.1?5.6, with propionyl chloride, to afford cis and trans 3-alkyl- 4-anilidopiperidines 6.1?6.6 (? 95 % yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the 1H-NMR spectra. Of the twelve synthesized 3-alkylfentanyls, ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (?)-cis-3-Me fentanyl 6.1cis, (8 x fentanyl), and the novel (?)-cis-3-Et fentanyl 6.2 cis, (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure- activity relationship (SAR) in this series of derivatives have been made.

Download Full-text

ChemInform Abstract: Synthesis and Structure Activity Relationships of cis- and trans-2,3,4, 4a,9,9a-Hexahydro-1H-indeno(2,1-c)pyridines for 5-HT Receptor Subtypes.

ChemInform ◽

10.1002/chin.199417171 ◽

2010 ◽

Vol 25 (17) ◽

pp. no-no

Author(s):

M. D. MEYER ◽

J. F. DEBERNARDIS ◽

A. A. HANCOCK

Keyword(s):

Receptor Subtypes ◽

Structure Activity Relationships ◽

Structure Activity ◽

Cis And Trans

Download Full-text

Antimicrobial Properties of Volatile Phenylpropanes

Natural Product Communications ◽

10.1177/1934578x1000500910 ◽

2010 ◽

Vol 5 (9) ◽

pp. 1934578X1000500 ◽

Cited By ~ 2

Author(s):

Alexander Pauli ◽

Karl-Heinz Kubeczka

Keyword(s):

Antimicrobial Activity ◽

Antimicrobial Properties ◽

Substitution Pattern ◽

Structure Activity Relationships ◽

Specific Effects ◽

Structure Activity ◽

Microbial Characteristics ◽

Cis And Trans Isomers ◽

Species Specific ◽

Cis And Trans

The examination of antimicrobial structure-activity relationships of 93 volatile phenylpropanes (VPs) and 21 related aromatic compounds revealed a dependence of antimicrobial activity from the kind and number of substituents on the aromatic ring, their substitution pattern and microbial characteristics, such as Gram coloring and strain specific factors. Eugenol isomers were predominantly inhibitory in a concentration range from 25 to 2000 mg/L against all microorganisms tested, which were three strains of Escherichia Coli and Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes, and Candida albicans. Etherified VPs were either less active or inactive depending on the type of side chain and/or substitution pattern. Differences in the antimicrobial activity of cis- and trans-isomers were observed. Species specific structure-activity relationships exist as was demonstrated with the Gram-negative bacteria (inactivity of E-ortho-eugenol) C. albicans (activity of di- and threefold methoxylated 1-propenylbenzenes), S. aureus and B. subtilis (activity of di-ortho methoxylated phenolic allylbenzenes and hydroquinone derivatives). With regard to the variety of observed specific effects and natural variation of susceptibility towards VPs according to literature reference data, the chances for successful prediction by computational analysis (QSAR) appear to be limited.

Download Full-text

Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpen Aminodiols

International Journal of Molecular Sciences ◽

10.3390/ijms21010184 ◽

2019 ◽

Vol 21 (1) ◽

pp. 184

Author(s):

Dániel Ozsvár ◽

Viktória Nagy ◽

István Zupkó ◽

Zsolt Szakonyi

Keyword(s):

Antiproliferative Activity ◽

Ring Opening ◽

Stereoselective Synthesis ◽

Click Reaction ◽

Substituent Effects ◽

Ring Closure ◽

Secondary Amines ◽

Structure Activity ◽

Cis And Trans ◽

Benzyl Substituent

A library of steviol-based trifunctional chiral ligands was developed from commercially available natural stevisoide and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate steviol methyl ester was prepared according to literature procedure. Depending on the epoxidation process, both cis- and trans-epoxyalcohols were obtained. Subsequent oxirane ring opening with primary and secondary amines afforded 3-amino-1,2-diols. The ring opening with sodium azide followed by a “click” reaction with alkynes resulted in dihydroxytriazoles. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. The resulting steviol-type aminodiols were tested against a panel of human adherent cancer cell lines (A2780, SiHa, HeLa, and MDA-MB-231). It was consistently found that the N-benzyl substituent is an essential part within the molecule and the ring closure towards N-benzyl substituted oxazolidine ring system increased the antiproliferative activity to a level comparable with that of cisplatine. In addition, structure–activity relationships were examined by assessing substituent effects on the aminodiol systems.

Download Full-text

Structure-Activity-Relationship and Bioactivity of Neurotrophic trans-Banglene

10.33774/chemrxiv-2021-0b2wc ◽

2021 ◽

Author(s):

Khyati Gohil ◽

M. Zain Kazmi ◽

Florence Williams

Keyword(s):

Kinase Inhibitors ◽

Signaling Proteins ◽

Structure Activity ◽

Cyclohexene Ring ◽

Pharmacokinetic Properties ◽

Living Organisms ◽

Neurotrophic Signaling ◽

Cis And Trans ◽

The Relationship ◽

Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, neurotrophin proteins possess pharmacokinetic properties that present challenges to their administration in living organisms, whether in biomedical studies or as therapeutics. Small molecules such as the cis- and trans-banglenes offer attractive alternatives to activate neurotrophic responses. We describe the synthesis and testing of banglene derivatives to establish a structure-activity response for the banglene family. Notably, during the course of our studies trans-banglene was shown to cause nerve growth factor (NGF)-potentiated neuritogenesis that was markedly stronger than the neuritogenic effects of trans-banglene alone. We demonstrate that only (–) trans-banglene is active, while its (+) enantiomer is not, and further demonstrate that select modifications on the cyclohexene ring of trans-banglene does not impair its bioactivity. Finally, to probe the relationship between (–) trans-banglene’s mechanism of ac-tion and canonical NGF signal transduction pathways, we employed kinase inhibitors targeting Pkc, Akt1/2/3 and Erk1/2, designed to inhibit NGF-induced neurotrophic signaling. Interestingly, (–) trans-banglene potentiation of NGF-induced neuri-togenesis was unaffected by the presence of these kinase inhibitors. Collectively, these results suggest a dual-mode of action for (–) trans-banglene (both neurotrophic alone and strongly potentiating of NGF activity), and an independence of its po-tentiating action on Pkc and Erk1/2 enzymatic activity.

Download Full-text

Structure-Activity Relationship and Bioactivity Studies of Neurotrophic trans-Banglene

10.33774/chemrxiv-2021-0b2wc-v3 ◽

2021 ◽

Author(s):

Khyati Gohil ◽

M. Zain Kazmi ◽

Florence Williams

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Signaling Proteins ◽

Neurotrophic Activity ◽

Structure Activity ◽

Cyclohexene Ring ◽

Pharmacokinetic Properties ◽

Pkc Inhibitors ◽

Cis And Trans ◽

Phenotypic Responses

Neurotrophic small molecule natural products are functional analogs of signaling proteins called neurotrophins, which cause a pro-growth, pro-survival, or pro-differentiation response in neuronal cells. While these phenotypic responses are desirable to combat neurodegenerative disease progression, the pharmacokinetic properties of neurotrophins present challenges to their administration. Therefore, neurotrophic small molecules such as the cis- and trans-banglenes offer attractive alternatives. We describe the synthesis and testing of banglene derivatives and establish a structure-activity response for the banglene family. We demonstrate that (–) trans-banglene is the primarily active enantiomer, and that select modifications on the cyclohexene ring of trans-banglene do not significantly impair its bioactivity. Finally, we demonstrate that (–) trans-banglene potentiation of NGF induced neuritogenesis is unaffected by the presence of these Erk1/2, Akt and Pkc inhibitors. Our structure-activity results also suggest that (–) trans-banglene neurotrophic activity and its potentiation of NGF activity might be distinct unassociated processes.

Download Full-text