Variety Of Substituents Research Articles

Potent MOR Agonists from 2′-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine

(−)-5,9-Dimethyl-6,7-benzomorphan (normetazocine) derivatives with a para-OH or ortho-F substituent in the aromatic ring of the N-phenethyl moiety were synthesized and found to have subnanomolar potency at MOR, and both were fully efficacious in vitro. These new compounds, (1R,5R,9R)-6,11-dimethyl-3-(2-fluorophenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol and (1R,5R,9R)-6,11-dimethyl-3-(4-hydroxyphenethyl)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol, were more potent than the unsubstituted compound N-phenethylnormetazocine and about 30 or 40 times more potent than morphine, respectively. A variety of substituents in the ortho, meta, or para position in the aromatic ring of the N-phenethyl moiety were synthesized, 25 of these compounds, and found to have varying effects on potency and efficacy as determined by the forskolin-induced cAMP accumulation assay. The N-phenethyl moiety was also modified by increasing chain length to form a N-phenylpropyl side chain with and without a para-nitro moiety, and by an N-cinnamyl side chain. Also, an indole ethylamine normetazocine was synthesized to replace the N-phenethylamine side chain in normetazocine. The phenylpropylamine, propenylamine (cinnamyl) and the para-nitropropylamine had little or no MOR potency. The indole-ethylamine on the normetazocine nucleus, however, had moderate potency (MOR EC50 = 12 nM), and was fully efficacious (%Emax = 102%) in the cAMP assay. Retention of the N-phenethyl moiety and the addition of alkyl and alkenyl moieties on C8 in (−)-N-phenethylnormetazocine gave a C8-methylene derivative that had subnanomolar potency at MOR and a C8-methyl analog that had nanomolar potency. Five C8-substituted compounds were synthesized.

Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potential.

The World Health Organization (WHO) reports that tuberculosis (TB) is one of the top 10 leading causes of global mortality. The increasing incidence of multidrug-resistant TB highlights the urgent need for an intensified quest to discover innovative anti-TB medications In this study, we investigated four new derivatives from the quinoxaline-2-carboxylic acid 1,4-dioxide class. New 3-methylquinoxaline 1,4-dioxides with a variation in substituents at positions 2 and 6(7) were synthesized via nucleophilic aromatic substitution with amines and assessed against a Mycobacteria spp. Compound 4 showed high antimycobacterial activity (1.25 μg/mL against M. tuberculosis) and low toxicity in vivo in mice. Selection and whole-genomic sequencing of spontaneous drug-resistant M. smegmatis mutants revealed a high number of single-nucleotide polymorphisms, confirming the predicted mode of action of the quinoxaline-2-carboxylic acid 1,4-dioxide 4 as a DNA-damaging agent. Subsequent reverse genetics methods confirmed that mutations in the genes MSMEG_4646, MSMEG_5122, and MSMEG_1380 mediate resistance to these compounds. Overall, the derivatives of quinoxaline-2-carboxylic acid 1,4-dioxide present a promising scaffold for the development of innovative antimycobacterial drugs.

A unique dual acyltransferase system shared in the polyketide chain initiation of kidamycinone and rubiflavinone biosynthesis.

The pluramycin family of natural products has diverse substituents at the C2 position, which are closely related to their biological activity. Therefore, it is important to understand the biosynthesis of C2 substituents. In this study, we describe the biosynthesis of C2 moieties in Streptomyces sp. W2061, which produces kidamycin and rubiflavinone C-1, containing anthrapyran aglycones. Sequence analysis of the loading module (Kid13) of the PKS responsible for the synthesis of these anthrapyran aglycones is useful for confirming the incorporation of atypical primer units into the corresponding products. Kid13 is a ketosynthase-like decarboxylase (KSQ)-type loading module with unusual dual acyltransferase (AT) domains (AT1-1 and AT1-2). The AT1-2 domain primarily loads ethylmalonyl-CoA and malonyl-CoA for rubiflavinone and kidamycinone and rubiflavinone, respectively; however, the AT1-1 domain contributed to the functioning of the AT1-2 domain to efficiently load ethylmalonyl-CoA for rubiflavinone. We found that the dual AT system was involved in the production of kidamycinone, an aglycone of kidamycin, and rubiflavinone C-1 by other shared biosynthetic genes in Streptomyces sp. W2061. This study broadens our understanding of the incorporation of atypical primer units into polyketide products.

Coupling-Spirocyclization Cascade of Tryptamine-Derived Isocyanides with Iodonium Ylides and Despirocyclization Reactions.

A cobalt(II)-catalyzed coupling-cyclization cascade reaction between tryptamine-derived isocyanides and iodonium ylides is investigated, which allowed for the synthesis of different types of spiroindoline compounds by variation of substituents at the N1- and C2-positions in the indole skeleton. More interesting is that the spiroindoline products could undergo despirocyclization in the presence of amines, enabling efficient construction of enamine compounds.

Regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone and its methylated analog using organometallic reagents

Herein, we report the regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone 2a and its methylated analog 2b, both of which contain a 6–7 fused carbocyclic enedione moiety. Nucleophilic additions to 2 using generic organometallic reagents, such as Grignard and organolithium reagents, preferentially occurs at the conjugated carbonyl group to afford a range of tert-alcohols with high stereoselectivity. The selectivity observed with 2 was notable when compared to that observed with Wieland–Miescher ketone 1a bearing a decalin framework. A variety of substituents, such as alkyl, alkenyl, alkynyl and aryl groups, can be introduced into 2 using this method. Exceptionally, the allylation reaction of 2 occurred at both the conjugated and non-conjugated carbonyl groups, but this regioselectivity problem was solved using organocopper reagents.

Facile synthesis and anticancer activity of tetrazolyl‐benzothiazole derivatives

AbstractWe herein reported a concise synthesis of a new class of tetrazolyl‐benzothiazoles (TBTs). This synthesis was achieved via a microwave‐assisted ANRORC method followed by an acid‐catalyzed [2 + 3] cycloaddition. The TBT core was elaborated with diverse substituents at the N‐1 or N‐2 position on the tetrazole ring to create a compound library for further bioactivity evaluation. The newly synthesized TBT‐based compounds were assessed for their inhibitory effects against human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Our results revealed that N‐2 substituted TBTs were generally more active than their N‐1 isomers, and 11g emerged as the most potent inhibitor with IC50 values of 5.3 and 10.4 μg/mL against MCF‐7 and MDA‐MB‐231, respectively. This study provides new insights into the synthesis and anticancer inhibitory activity of TBTs, highlighting their potential for future drug development.

Design and synthesis of a library of C2-substituted sulfamidoadenosines to probe bacterial permeability

Antibiotic resistance is a major threat to public health, and Gram-negative bacteria pose a particular challenge due to their combination of a low permeability cell envelope and efflux pumps. Our limited understanding of the chemical rules for overcoming these barriers represents a major obstacle in antibacterial drug discovery. Several recent efforts to address this problem have involved screening compound libraries for accumulation in bacteria in order to understand the structural properties required for Gram-negative permeability. Toward this end, we used cheminformatic analysis to design a library of sulfamidoadenosines (AMSN) having diverse substituents at the adenine C2 position. An efficient synthetic route was developed with installation of a uniform cross-coupling reagent set using Sonogashira and Suzuki reactions of a C2-iodide. The potential utility of these compounds was demonstrated by pilot analysis of selected analogues for accumulation in Escherichia coli.

Anti-Inflammatory Activities of 8-Benzylaminoxanthines Showing High Adenosine A2A and Dual A1/A2A Receptor Affinity.

Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson's disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential anti-inflammatory activity. The compounds were investigated in radioligand binding studies at all four human adenosine receptor subtypes, A1, A2A, A2B and A3. Compounds showing nanomolar A2A and dual A1/A2A affinities were obtained. Three compounds, 19, 22 and 24, were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A1 and A2A receptors. In vitro studies confirmed the high metabolic stability of the compounds, and the absence of toxicity at concentrations of up to 12.5 µM in various cell lines (SH-SY5Y, HepG2 and BV2). Compounds 19 and 22 showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 24 as the most potent anti-inflammatory derivative. Future studies are warranted to further optimize the compounds and to explore their therapeutic potential in neurodegenerative diseases.

Synthesis and antimalarial activity of novel 3-substituted chloroquine derivatives

The synthesis and characterization of a series of new 3-substituted chloroquine (CQ) derivatives are reported along with their antimalarial activity against CQ-sensitive, 3D7, and CQ-resistant, Dd2, strains of Plasmodium falciparum. The new CQ derivatives stem from the aroylation of 3-aminochloroquine, which in turn is prepared in four efficient steps from 4,7-dichloroquinoline. Variation of the aroylation substituents and ring substitution patterns reveal that 4-substitution with electron-withdrawing moieties results in the lowest IC50 values, both in the same order of magnitude as CQ itself for the 3D7 strain. Given its activity against the resistant Dd2 strain, the 4-chlorobenzamido-CQ derivative is chosen as the lead compound for potential use in combination therapy.

Synthesis and Photophysical Properties of Charge-Transfer-Based Pyrimidine-Derived α-Amino Acids.

The four-step synthesis of fluorescent pyrimidine-derived α-amino acids from an l-aspartic acid derivative is described. The key synthetic steps involved preparation of ynone intermediates via the reaction of alkynyl lithium salts with a Weinreb amide, followed by an ytterbium-catalyzed heterocyclization reaction with amidines. Variation of substituents at the C2- and C4-position of the pyrimidine ring allowed tuning of the photoluminescent properties of the α-amino acids. This revealed that a combination of highly conjugated or electron-rich aryl substituents with the π-deficient pyrimidine motif resulted in fluorophores with the highest quantum yields and overall brightness. Further analysis of the most fluorogenic α-amino acid demonstrated solvatochromism and sensitivity to pH.

Recent Progress on Nitrogen-Rich Energetic Materials Based on Tetrazole Skeleton.

Development of nitrogen-rich energetic materials has gained much attention because of their remarkable properties including large nitrogen content and energy density, good thermal stability, low sensitivity, good energetic performance, environmental friendliness and so on. Tetrazole has the highest nitrogen and highest energy contents among the stable azoles. The incorporation of diverse explosophoric groups or substituents into the tetrazole skeleton is beneficial to obtain high-nitrogen energetic materials having excellent energetic performance and suitable sensitivity. In this review, the development of high-nitrogen energetic materials based on tetrazole skeleton is highlighted. Initially, the property and utilization of nitrogen-rich energetic materials are presented. After showing the advantage of the tetrazole skeleton, the high-nitrogen energetic materials based on tetrazole are classified and introduced in detail. Based on different types of energetic materials (EMs), the synthesis and properties of nitrogen-rich energetic materials based on mono-, di-, tri- and tetra-tetrazole are summarized in detail.

Thiadiazine thione derivatives as anti-leishmanial agents: synthesis, biological evaluation, structure activity relationship, ADMET, molecular docking and molecular dynamics simulation studies

During last decades, 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1H-NMR, 13C-NMR and Mass spectrometry, and finally evaluated against Leishmania major. Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC50 values of (2.17 μM), (2.39 μM), (2.00 μM), and (1.39 μM), respectively even better than the standard amphotericin B (IC50 = 0.50) and pentamidine (IC50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major. Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major. Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski’s rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future. Communicated by Ramaswamy H. Sarma

Gold and Palladium Relay Catalytic [4 + 4] Cycloadditions of Enynamides and γ-Methylene-δ-valerolactones: Diastereoselective Construction of Furan-Fused Azacyclooctanes.

We report a highly efficient and diastereoselective gold and palladium sequential relay catalysis system for the synthesis of furan-fused eight-membered heterocycles. Employing a one-pot procedure, easily accessible enynamides undergo cyclization to generate azadienes in situ, which subsequently participate in diastereoselective formal [4 + 4] cycloadditions with γ-methylene-δ-valerolactones. This strategy enables the rapid and efficient construction of a series of furan-fused azacyclooctanes with diverse substituents in good yields (63-97%) and a high level of diastereoselectivity (7:1 → 20:1 dr).

Exploration of charge transfer analysis and photovoltaics properties of A-D-A type non-fullerene phenazine based molecules to enhance the organic solar cell properties

To intensify the photovoltaic properties of organic solar cells, density functional theory (DFT) based computational techniques were implemented on six non-fullerene A-D-A type small molecules (N1–N6) modified from reference molecule (R) which consists of phenazine fused with 1,4- Dimethyl-4H-3,7-dithia-4-aza- cyclopenta [α] pentalene on both sides with one of its phenyl rings acting as the central donor unit, further attached with 2-(5,6-Difluoro-2-methylene-3-oxo-indan-1-ylidene)-malononitrile acceptor groups at terminal sites. All proposed compounds have a phenazine base modified with a variety of substituents at the terminals. Transition density matrix, density of states, frontier molecular orbitals, intramolecular charge transfer abilities and optoelectronic properties of these compounds were investigated using B3LYP/6-31G (d, p) and B3LYP/6-31G++ (d,p) level of theory. All six designed compounds exhibited a bathochromic sift in their λmax as compared to the R molecule. All designed molecules also have reduced band gap and smaller excitation energy than R. Among all, N6 exhibited highest λmax and lowest bandgap as compared to reference molecule indicating its promising photovoltaic properties. Decreased hole and electron reorganization energy in several of the suggested compounds is indicative of greater charge mobility in them. PTB7-Th donor was employed to calculate open circuit voltage of all investigated molecules. N1–N5 molecules had improved optoelectronic properties, significant probable power conversion efficiency as evident from their absorption aspects, high values of Voc, and fill factor, compared to R molecule. Designed A-D-A type NF based molecules make OSCs ideal for use in wearable devices, building-integrated photovoltaics and smart fabrics.

Divergent synthesis of benzo[b]phosphole oxide derivatives focusing on substituents on phosphorus atom

Synthesis of benzo[b]phosphole oxide derivatives having a variety of diverse substituents on the phosphorus atom was achieved by using a corresponding cyclic ethyl phosphinate as a key synthetic intermediate. The photophysical properties of these compounds were found to be dependent upon the electronic nature of the substituents.

Synthesis of Naphthalimides through Tandem Pd(II)-Catalyzed C(sp3)-H Oxidation and Diels-Alder Reaction Using a Transient Directing Group Strategy.

Naphthalimides have found extensive applications in materials science and pharmaceuticals. It is still highly desirable to develop efficient methods for the synthesis of naphthalimides with structural diversity. In this work, we developed a new approach for the synthesis of naphthalimides via a tandem reaction of o-methylbenzaldehydes and maleimides. The tandem reaction involves Pd(II)-catalyzed benzylic C(sp3)-H oxidation using an amino acid as the transient directing group and Diels-Alder reaction. The subsequent dehydration forms naphthalimides. The reaction introduces the imide moiety and constructs a benzene ring simultaneously, allowing for easy access to a range of naphthalimides with a variety of substituents.

Synthesis, Structural Identification and Biological Potencies of Quinolinium Sulfonamide Ionic Liquids

Members of the quinoline family include several alkaloids. Alkaloids are found in foods and beverages that humans consume daily and in various stimulants. Among many other activities, they act against inflammation, cancer, bacteria, fungi and pain. Modifications of the alkyl chain after N-alkylation can alter the physicochemical properties and affect its multifunctional properties. This article describes the preparation and structural identification of five quinolinium sulfonamide ionic liquids that differ in N-alkylation functional group and chain length. Functional group and alkyl chain length in the N-alkylation of ionic liquids of quinolinium sulfonamide ionic liquids significantly affected the antioxidant activity and C-1 showed the highest antioxidant activity with the lowest IC50 of 20.56. Variation of substituents in the N-alkylation of ionic liquids of quinolinium sulfonamide also significantly affected its antibacterial and antifungus activity, with C-1 exhibiting the greatest activity. In addition, experimental results indicate that quinolinium sulfonamide ionic liquids significantly prolong normal human plasma’s prothrombin time (PT).

Synthesis of Naturally Racemic Marilines B & C through Multicomponent Reactions Involving ortho-Quinone Methides and Various Nitrogen Nucleophiles

AbstractHerein, we report the first total synthesis of (±)-marilines B and C, as well as a failed approach to (±)-mariline A, by using our recently developed multicomponent reaction method, which involves the interception of ortho-quinone methides with various nitrogen nucleophiles to allow easy assembly of various benzylic amine cores with diverse substituents.

Synthesis of Hybrid Ligands with Nitrile and Cage Phosphane Donor Groups and their Applications in Gold-Mediated Reactions.

Altering the donor properties of phosphane ligands through substituent variation is an established tool in coordination chemistry and catalysis. This contribution describes the synthesis of two new hybrid donors (L) combining 1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane-8-yl (PCg) and nitrile donor groups at different molecular scaffolds, viz. ferrocene-1,1'-diyl (fc) and 1,2-phenylene. These ligands were used to prepare dimeric Au(I) complexes [Au2 (μ(P,N)-L)2 ][SbF6 ]2 , which were evaluated as silver-free, preformed catalysts in Au-mediated cycloisomerization of (Z)-3-methylpent-2-en-4-yn-1-ol to 2,3-dimethylfuran. The catalyst featuring the ferrocene-based ligand, viz., [Au2 (μ(P,N)-CgPfcCN)2 ][SbF6 ]2 , showed the best catalytic performance at low catalyst loading (0.5 or 0.15 mol.%), which exceeded that of its diphenylphosphanyl analog [Au2 (μ(P,N)-Ph2 PfcCN)2 ][SbF6 ]2 studied earlier and the prototypical Au(I) precatalyst [Au(PPh3 )(MeCN)][SbF6 ].

Halochromic properties of new nitrophenol-based azochromophores

A number of new azo dyes were synthesized using azo-coupling of nitrohydroxyphenols (2-nitroresorcinol and nitrophloroglicinol) with ortho-aminophenol and its nitro- and sulfonic-substituted derivatives. The dye molecules contain multiple hydroxy groups which can be easily deprotonated, and their ionization affects the conjugated π-electron system of the dye molecule leading to the significant spectral changes. Spectrophotometric titration of the obtained dyes with an acid and an alkali revealed their halochromic behaviour, i.e. an ability to alter color upon pH change. All the dyes absorb light with wavelength shorter 500 nm in acidic media, and with wavelength longer 500 nm in alkaline media. Variation of substituents in the dye molecules allows to tune the pH range of the color change. The obtained dye series covers the pH range from 0 to 10. DFT calculations of the dye molecules revealed their structures and preferential isomeric forms. TD-DFT calculations of the excited states allowed to clarify the acid-base equilibrium based on the spectrophotometric titration, and to determine the nature of the observed absorption bands. The dyes were adsorbed on polyamide fabrics, and the dyed fabrics reversibly changed their color upon treating with acids and alkalis. These fabrics with applied dyes showed good resistance to aggressive environments and mechanical influences. Results of tests of the dyed fabrics showed that the obtained materials can be used as flexible textile pH sensors.