Amide Substitution Research Articles

Effect of the Nature of Donor Atoms on the Thermodynamic, Kinetic and Relaxation Properties of Mn(II) Complexes Formed With Some Trisubstituted 12-Membered Macrocyclic Ligands.

During the past few years increasing attention has been devoted to Mn(II) complexes as possible substitutes for Gd(III) complexes as contrast agents in MRI. Equilibrium (log KMnL or pMn value), kinetic parameters (rates and half-lives of dissociation) and relaxivity of the Mn(II) complexes formed with 12-membered macrocyclic ligands were studied. The ligands were selected in a way to gain information on how the ligand rigidity, the nature of the donor atoms in the macrocycle (pyridine N, amine N, and etheric O atom), the nature of the pendant arms (carboxylates, phosphonates, primary, secondary and tertiary amides) affect the physicochemical parameters of the Mn(II) complexes. As expected, decreasing the denticity of DOTA (to afford DO3A) resulted in a drop in the stability and inertness of [Mn(DO3A)]− compared to [Mn(DOTA)]2−. This decrease can be compensated partially by incorporating the fourth nitrogen atom into a pyridine ring (e.g., PCTA) or by replacement with an etheric oxygen atom (ODO3A). Moreover, the substitution of primary amides for acetates resulted in a noticeable drop in the stability constant (PC3AMH), but it increased as the primary amides (PC3AMH) were replaced by secondary (PC3AMGly) or tertiary amide (PC3AMPip) pendants. The inertness of the Mn(II) complexes behaved alike as the rates of acid catalyzed dissociation increased going from DOTA (k1 = 0.040 M−1s−1) to DO3A (k1 = 0.45 M−1s−1). However, the rates of acid catalyzed dissociation decreased from 0.112 M−1s−1 observed for the anionic Mn(II) complex of PCTA to 0.0107 M−1s−1 and 0.00458 M−1s−1 for the cationic Mn(II) complexes of PC3AMH and PC3AMPip ligands, respectively. In spite of its lower denticity (as compared to DOTA) the sterically more hindered amide complex ([Mn(PC3AMPip)]2+) displays surprisingly high conditional stability (pMn = 8.86 vs. pMn = 9.74 for [Mn(PCTA)]−) and excellent kinetic inertness. The substitution of phosphonates for the acetate pendant arms (DOTP and DO3P), however, resulted in a noticeable drop in the conditional stability as well as dissociation kinetic parameters of the corresponding Mn(II) complexes ([Mn(DOTP)]6− and [Mn(DO3P)]4−) underlining that the phosphonate pedant should not be considered as a suitable building block for further ligand design while the tertiary amide moiety will likely have some implications in this respect in the future.

Pyrrole β-amides: Synthesis and characterization of a dipyrrinone carboxylic acid and an N-Confused fluorescent dipyrrinone

Pyrrole β-amides are useful building blocks for the preparation of novel molecular architectures that can be used in supramolecular chemistry and sensor development. Under basic conditions, pyrrole β-amides with an α-aldehyde produce different condensation products when reacted with pyrrolinones depending on the amide substitution. Secondary amides form the expected dipyrrinones, but unexpectedly undergo a subsequent trans-amidation with the pyrrolinone nitrogen to produce an unsymmetrical imide (an N-confused fluorescent dipyrrinone). Under the same conditions, tertiary amides produce the expected dipyrrinone carboxylic acids, which have been shown to have strong self-association properties as determined by vapor pressure osmometry measurements, NMR studies, and X-ray crystal structure determination. Furthermore, an N-confused fluorescent dipyrrinone was produced from the same trans-amidation reaction during attempts to decarboxylate a dipyrrinone amide with a 9-carboxylic moiety.

Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents

3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.

Fabrication of Multifunctional 2,5-Di(2-Thienyl) Pyrrole Based Conducting Copolymer for Further Sensor and Optoelectronic Applications

In this work a multifunctional amid substituted 2,5-di(2-thienyl)pyrrole derivative (BTP), has been synthesized. The synthesized monomer has unique properties for improving the optical and electrical properties of its conductive polymer. The amide substitution in the monomers provides an effective delocalization of the π-bonds by forcing the conjugated thienylpyrrole electroactive group into the more planar structure. This improves the optical and electrical properties of the conductive polymer. Moreover, electropolymerization has resulted in a cross-linked conductive polymer with three-dimensional conductivity as the monomer structure contains two electroactive groups. Finally, the amine group in the structure allows for further functionalization of the conducting polymer and its use in various sensor platforms. Furthermore, the synthesized monomer (BTP) has been copolymerized with EDOT using different monomer feed ratios and the properties of the copolymer have been investigated in comparison with the homopolymer. Electrochromic devices have constructed with the obtained polymer and it has been determined that constructed device has a high optical contrast and stability when compared with other 2,5-di(2-thienyl)pyrrole derivatives in the literature.

Synthesis, Characterization and Biological Activities of Creatinine Amides and Creatinine Schiff Bases.

In spite of substantial progress in scientific cognizance and medical technology, still infectious diseases are among the leading cause of morbidity and mortality. Creatinine and Schiff bases are well known for their diverse range of biological activities and thought to be emerging and useful therapeutic target for the treatment of several diseases. The present work was aimed to illustrate the influence of substitution of amides and Schiff bases on creatinine and their antimicrobial, antioxidant and anti-urease effectiveness was determined. Creatinine substituted amides (1-2) and creatinine Schiff bases (3-7) were synthesized and characterized by NMR and IR spectral data in combination with elemental analysis. All the compounds (1-7) were investigated on Jack bean urease for their urease inhibitory potential. Investigation of antimicrobial activity of the compounds was made by the agar dilution method. Moreover, 1,1-diphenyl-2- picrylhydrazyl (DPPH) method was used to determine their antioxidant potential. Molecular docking studies were also carried out to elucidate their relationship with the binding pockets of the enzyme. The compounds were found to be potent inhibitors of urease. The synthesized derivatives exhibited significant inhibition against Gram-positive and Gram-negative bacterial strains, as compared to standard, ciprofloxacin. Creatinine based derivatives exhibited potential antifungal activity when tested on infectious and pathogenic fungal strains. Similarly, most of the compounds exhibited good antioxidant activity. These derivatives may serve as a source of potential antioxidants and also help to retard microbial growth in food industry. Similarly, the studies provide a basis for further research to develop more potent urease inhibitory compounds of medicinal /agricultural interest.

Turning on the red phosphorescence of a [Ru(tpy)(bpy)(Cl)]Cl complex by amide substitution: self-aggregation, toxicity, and cellular localization of an emissive ruthenium-based amphiphile.

Coupling the notoriously non-emissive complex [Ru(tpy)(bpy)Cl]Cl (tpy = 2,2':6',2''-terpyridine, bpy = 2,2'-bipyridine) to a C12 alkyl chain via an amide linker on the 4' position of the terpyridine yielded a new amphiphilic ruthenium complex showing red emission and chloride-dependent aggregation properties. This emissive complex is highly cytotoxic in A549 non-small lung cancer cells where it can be followed by confocal microscopy. Uptake occurs within minutes, first by insertion into the cellular membrane, and then by migration to the peri-nuclear region.

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit

We have synthesized and characterized MP-III-022 ((R)−8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABAA receptors containing the α5 subunit (α5GABAARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1–10mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABAA receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2′F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10–200mg/kg), but at the price of activating non-α5 GABAARs as well as the desired α5GABAARs at the highest dose. At the dose of 10mg/kg, which elicits a strong positive modulation of α5GABAARs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1–10mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABAARs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.

A DOTAM‐based paraCEST agent favoring TSAP geometry for enhanced amide proton chemical shift dispersion and temperature sensitivity

The Tm(3+) chelate of DOTAM [1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane] possessing sterically demanding t-butyl amide substitution favors TSAP geometry. This chelate displayed a paraCEST signal associated with the highly shifted amide proton signal at approximately -100 ppm that was beyond the frequency of macromolecule magnetization transfer. This signal also displayed high temperature dependence (0.57 ppm °C(-1)) in the range of 35-42 °C and at neutral pH.

N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections

Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity.

Complementary regioselectivity in the synthesis of iminohydantoins: remarkable effect of amide substitution on the cyclization

Complementary regioselective synthesis of iminohydantoins from isocyanoacetamides controlled by the substituent on the amide group has been described. 4-Iminohydantoins were the major products when the starting materials were N-alkyl isocyanoamides, whereas 2-iminohydantoins were the major products with N-aryl isocyanoamides.

Remarkable effects of primary amide substitution in the sensitizer: an efficient route to enhance the photocurrent density of the solar cell

The incorporation of electron-withdrawing groups in carbene based ruthenium complexes significantly affected their light-harvesting capabilities. The remarkable increase in the conversion efficiency was exhibited by the primary amide substituted sensitizer, CI103 (9.32%), compared to that of CI101 (5.44%) and the N719 dye (8.43%). The finding gives an efficient approach to enhance the photocurrent density and the power conversion efficiency of the solar cell.

Anti-AIDS Agents 90. Novel C-28 Modified Bevirimat Analogues as Potent HIV Maturation Inhibitors

In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC(50) of 0.0059 μM compared with 0.087 μM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.

Voltammetric Oxidation of 2-Oxo-1,2,3,4-tetrahydropyrimidin-5-carboxamides: Substituent Effects

Electrochemical oxidation of a series of 20 substituted 2-oxo-1,2,3,4-tetrahydropyrimidin-5-carboxamides (THPMs) in acetonitrile has been studied using voltammetric methods at a glassy carbon electrode to investigate the influence of the substituents on the 4- and 5-positions of the heterocyclic ring. Analysis of the results shows that the electronic nature and steric hindrance of the substituents, especially their orientations toward the heterocyclic ring, determine their effects on the oxidation potential. Analysis of the computational results obtained at the DFT-B3LYP/6-31++G** level of theory suggests a mechanism in which the first electron removal occurs from either the N(1) of the heterocyclic ring or N(17) of the amide substitution. This process is followed by a fast proton removal resulting in the formation of stable allylic and/or benzylic radicals which then undergo further oxidation to the 2-oxo-1,2-dihydropyrimidin-5-carboxamides (DHPMs).

Synthesis of highly substituted amide hyaluronan derivatives with tailored degree of substitution and their crosslinking via click chemistry

Hyaluronan (HA) based hydrogels with well defined 3D-molecular architecture have been synthesized combining chemical modification of hyaluronic acid and ‘click chemistry’. The high degree of substitution of HA was obtained after activation of the carboxyl group with ethyl chloroformate and subsequent functionalization of the carboxylic group with primary amine containing either a terminal azido or alkynyl groups. The degree of amide substitution could be controlled by reaction conditions. The chemical modification probed to be highly chemo-selective providing only amide modified HA derivates. The prepared derivates showed higher resistance towards thermal degradation than starting hyaluronan material. The crosslinking reaction of azido- and alkynyl-amide derivates of HA led to the formation of highly organized and porous networks, which due to their high stability against degradation are potential candidates for application as drug delivery systems, or scaffolds in tissue engineering.

Synthesis of New .ALPHA.-Glucosidase Inhibitors Based on Oleanolic Acid Incorporating Cinnamic Amides

A series of α-glucosidase inhibitors with the oleanolic acid core and different cinnamic amide ligands were designed and synthesized. Their preliminary structure-activity relationships were analyzed. In general, the compounds with 3,28-disubstituted oleanolic acid exhibited stronger activity than those 28-monosubstituted analogues, and variation of cinnamic amide substitution significantly affected α-glucosidase inhibition activities. Most of the compounds showed potent inhibitory activity against α-glucosidase with much greater efficacy than a typical α-glucosidase inhibitor, acarbose.

Bistable or Oscillating State Depending on Station and Temperature in Three‐Station Glycorotaxane Molecular Machines

High-yield, straightforward synthesis of two- and three-station [2]rotaxane molecular machines based on an anilinium, a triazolium, and a mono- or disubstituted pyridinium amide station is reported. In the case of the pH-sensitive two-station molecular machines, large-amplitude movement of the macrocycle occurred. However, the presence of an intermediate third station led, after deprotonation of the anilinium station, and depending on the substitution of the pyridinium amide, either to exclusive localization of the macrocycle around the triazolium station or to oscillatory shuttling of the macrocycle between the triazolium and monosubstituted pyridinium amide station. Variable-temperature (1)H NMR investigation of the oscillating system was performed in CD(2)Cl(2). The exchange between the two stations proved to be fast on the NMR timescale for all considered temperatures (298-193 K). Interestingly, decreasing the temperature displaced the equilibrium between the two translational isomers until a unique location of the macrocycle around the monosubstituted pyridinium amide station was reached. Thermodynamic constants K were evaluated at each temperature: the thermodynamic parameters DeltaH and DeltaS were extracted from a Van't Hoff plot, and provided the Gibbs energy DeltaG. Arrhenius and Eyring plots afforded kinetic parameters, namely, energies of activation E(a), enthalpies of activation DeltaH( not equal), and entropies of activation DeltaS( not equal). The DeltaG values deduced from kinetic parameters match very well with the DeltaG values determined from thermodynamic parameters. In addition, whereas signal coalescence of pyridinium hydrogen atoms located next to the amide bond was observed at 205 K in the oscillating rotaxane and at 203 K in the two-station rotaxane with a unique location of the macrocycle around the pyridinium amide, no separation of (1)H NMR signals of the considered hydrogen atoms was seen in the corresponding nonencapsulated thread. It is suggested that the macrocycle acts as a molecular brake for the rotation of the pyridinium-amide bond when it interacts by hydrogen bonding with both the amide NH and the pyridinium hydrogen atoms at the same time.

Polyamidoamine dendrimer and dextran conjugates: preparation, characterization, and in vitro and in vivo evaluation

AbstractAmide and ester conjugates of aceclofenac with polyamidoamine (PAMAM-G0) dendrimer zero generation and dextran (40 kDa) polymeric carrier, respectively, are presented. The prepared conjugates were characterized by UV, TLC, HPLC, IR, and 1H NMR spectroscopy. The average degrees of substitution of amide and ester conjugates were determined and found to be (12.5 ± 0.24) % and (7.5 ± 0.25) %, respectively. The in vitro hydrolysis studies showed that dextran ester conjugate hydrolyzed faster in a phosphate buffer solution of pH 9.0 as compared to PAMAM dendrimer G0 amide conjugate, and followed the first order kinetics. No amount of the drug was regenerated at pH 1.2 in simulated gastric fluid. The dextran conjugate showed short half-life as compared to the PAMAM dendrimer conjugate. Anti-inflammatory and analgesic activities of the dendrimer conjugate were found to be similar to those of the standard drug. Results of chronic ulceroginic activity showed deep ulceration and high ulcer index for aceclofenac, whereas lower ulcer index was found for the PAMAM dendrimer and dextran (40 kDa) conjugates. Experimental data suggest that PAMAM dendrimer and dextran (40 kDa) can be used as carriers for the sustained delivery of aceclofenac along with a remarkable reduction in gastrointestinal toxicity.

Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549-NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-κB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-κB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 μM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-κB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going.

Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors

A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.

Design of Peptide-based Inhibitors for Human Immunodeficiency Virus Type 1 Strains Resistant to T-20

Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.