Modification Of Substituents Research Articles

A new class of histamine H(3)-receptor antagonists: synthesis and structure-activity relationships of 7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolines.

The synthesis and biological evaluation of novel cycloheptaquinoline antagonists of the human H(3) receptor are described. Two series of compounds, bearing either an amino substituent or an alkyne linker at the 11-position, were investigated. Modifications of the amino substituents, optimization of chain length and the effect of conformational restraints are described. Several compounds with high affinity and selectivity for the H(3) receptor were discovered.

Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents

We recently reported the first benzoic acid, 1-[4-carboxy-2-(3-pentylamino)phenyl]-5,5-bis(hydroxymethyl)pyrrolidin-2-one (8), that is a potent inhibitor of avian influenza A neuraminidase (N9) and, unlike other reported potent neuraminidase inhibitors, does not contain a basic aliphatic amine or guanidine nor a simple N-acetyl grouping. However, 8 was a poor inhibitor of influenza B neuraminidase. In the present study we further evaluated 8 as an inhibitor of human influenza A NA isolates, and it was effective against N2NA but found to be 160-fold less active against N1NA. We also synthesized analogues of 8 involving moderate modifications of essential substituents on the pyrrolidinone ring. Specifically, the aminomethyl (9), hydroxyethyl (10), and aminoethyl (11) analogues were prepared. Only the most conservative change (compound 9) resulted in continued effective inhibition of influenza A, in addition to a noteworthy increase in the activity of 9 for N1NA. The effectiveness of 9 against influenza B neuraminidase was furthermore improved 10-fold relative to 8, but this activity remained 50-fold poorer than for type A NA.

Synthesis of Novel Titanasiloxanes with Ring and Cage Structures Using Sterically Demanding Substituents

Novel oligomeric titanasiloxanes have been synthesized in good yields by reaction of sterically demanding organosilanetriols with titanium alkoxides. The silanetriols Bu-t(2)(Me3Si)FlSi(OH)(3) (5), (Me3Si)FlSi(OH)(3) (6), and MeFlSi(OH)(3) (7) and the titanium alkoxides Ti((OEt)-Et-i)(4), Ti((OPr)-Pr-i)(4), and Ti((OPr)-Pr-i)(2)(acac)(2) have been used as starting materials (Fl = fluorenyl). Quite different structures are obtained by only small modifications of the organic substituents of the substrates. Thus, the condensation reactions result in the formation of the polyhedral titanasiloxanes [Bu-t(2)(Me3Si)FlSi](4)O-12[TiOEt](4) (8), [(Me3Si)FlSi](2)O-5[Ti(OEt)](4) /mu(2)-OEt](6) [mu(4)-O] (9), ([Bu-t(2)(Me3Si)FlSi](3)O-10[Ti((OPr)-Pr-i)](4) [mu(2)-OiPr](2) [mu(3)-O]Ti)(2)O (10), and [MeFlSi](2)O-8[Ti((OPr)-Pr-i)](6)(-) [mu(2)-(OPr)-Pr-i](4)[mu(3)-O](2)[PhNH2](2) (11) and the cyclic titanasiloxane [MeFlSi((OPr)-Pr-i)](2)O-4[Ti(acac)(2)](2) (12). A 1:1 stoichiometry of the starting materials leads to 8 and 12 in quantitative yield, while 9-11 are isolated in minor quantities. If the appropriate substrate ratio is used, the latter compounds can also be obtained in high yields. All titanasiloxanes have been characterized by X-ray crystallography, NMR, IR, and elemental analysis.

Compounds with Phosphorus at the Spiro Position

Publisher Summary Four coordinate phosphorus can occupy a spiro position to form compounds analogous to the corresponding quaternary ammonium compounds. There are a number of six coordinate spiro phosphorus compounds. Compounds which have interactions completing the spiro system have been included in this chapter. Theoretical methods are first discussed. Experimental structural methods include X-ray diffraction, magnetic resonance, spectrometry, spectroscopy, polarization, and polarimetry. Thermodynamic aspects and reactivity of fully conjugated rings are elaborated in the chapter. An analysis of spirophospanium salts and ylides, spirophosporanes, and spiroperphosphoranides are presented in detail. Reactivity of substituents attached to ring carbon, and that of substituents attached to ring heteroatoms including spirophosphorus are also described. Ring synthesis includes all acyclic components, cycloaddition, substituent modification, ring modification, and other methods. The section on important compounds and applications consists of nonmedical applications and compounds of medical interest. A series of bis cyclotriphosphazenyl spermines have been prepared and revealed to have anticancer activity in six murine tumour systems. Spirophosphorane derivatives of thymidine have been used as models for the study of the stereochemistry of cyclic AMP interactions with enzymes in the chapter.

Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists.

Starting from dopamine receptor ligand BP897, an interactive drug discovery process leading to heterocyclic bioisosteres is demonstrated. The four step strategy involved a careful optimization of geometric and electronic properties by systematic modification of the attachment points and heteroatoms, respectively. Efficacy tuning by modification of the phenyl substituents led to both D3 partial agonists and full antagonists. The benzothiophenes 3c (FAUC346) and 3d (FAUC365) revealed outstanding D3 affinity and subtype selectivity.

Studies of substituent effects on the electronic structure and related properties of [Ru(phen)3]2+ with DFT method

Studies on the complex [Ru(phen)3]2+ (phen=1,10-phenanthroline) and its 5,6-di-substituted derivates are carried out using DFT method and B3LYP/LanL2DZ level of theory. The trends in the substituent modification effects caused by the electron-pushing group (OH) and the electron-withdrawing group (F), on the electronic structure and related properties, e.g. the components and the energies of some frontier molecular orbitals, the spectroscopy characteristics, and the net charge populations of some main atoms of the complexes, etc, have been investigated. The computational results show: First, the substituents have some interesting effects on the excited state characteristics of complexes. For the excited states of the complexes, the electron-withdrawing group (F) can activate the main ligand and passivate the co-ligands, whereas the electron-pushing group (OH) can activate different sites of the main ligand (relative to the ground state). Second, both the electron-pushing group (OH) and the electron-withdrawing group (F) can cause a red shift in the electronic ground band. Third, the following characteristics of the atomic charge populations can been seen: Along path (a) R→C5→C12→C11→N1, the atomic negative charges fully alternate with the atomic positive charges for I (ROH) and III (RF), and the extent of alternation is greater for III than for I. However, such a atomic charge alternation does not obviously exist for II (RH). Along path (b) R→C5→C12→C4→C3→C2→N1, the atomic charge populations incompletely show alternation for I and III. Changing substituent R can greatly influence charge populations on its neighboring atoms, but it only slightly influences those on farther atoms. Such complicated characteristics of the charge populations in the complexes can be explained by the law of polarity alternation and the idea of polarity interference.

2-Aryl indole NK 1 antagonists: optimisation of the amide substituent

The in vivo properties of a series of 2-arylindole NK 1 antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.

Novel 4,1-benzoxazepine derivatives with potent squalene synthase inhibitory activities

A series of (3,5- trans)-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine derivatives were synthesized and evaluated for squalene synthase inhibitory and cholesterol biosynthesis inhibitory activities. Through modification of substituents of the lead compounds 1a and 1b, it was found that 4,1-benzoxazepine-3-acetic acid derivatives with isobutyl and neopentyl groups at the 1-position, the chloro atom at the 7-position, and the chloro and methoxy groups at the 2′-position on the 5-phenyl ring, had potent squalene synthase inhibitory activity. Among such compounds, the 5-(2,3-dimethoxyphenyl) derivative 2t exhibited potent inhibition of cholesterol biosynthesis in HepG2 cells. As a result of optical resolution study of 2t, the absolute stereochemistry required for inhibitory activity was determined to be 3 R,5 S. In vivo study showed that the sodium salt of (3 R,5 S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid 20 effectively reduced plasma cholesterol in marmosets.

The inhibition and selectivity of bacterial topoisomerases by BMS-284756 and its analogues.

Analogues of BMS-284756, a novel des-F(6)-quinolone, were synthesized and evaluated in order to determine the effects of modification of substituents on in vitro target inhibition. BMS-340281 (stereoisomer of BMS-284756), BMS-340280 (C-6 fluorinated analogue of BMS-284756), BMS-340278 (C-8-H derivative), BMS-433366 (C-8 methoxy analogue) and fluoroquinolone comparators were evaluated for antibacterial activity. The MICs of BMS-284756 were generally found to be within two-fold of the MICs of BMS-284756 analogues against a panel of Gram-positive and -negative organisms. BMS-284756 had MICs of 0.03-0.125 mg/L against Streptococcus pneumoniae strains with GyrA and ParC mutations, and was the most active quinolone. BMS-284756 and its analogues had similar activity compared with ciprofloxacin and moxifloxacin against topoisomerase IV decatenation, but were three times more active than levofloxacin. The IC(50) of BMS-284756 for human topoisomerase II (hTopo II) was 3000 times higher than its IC(50) for DNA gyrase, and no whole-cell cytotoxicity was noted. Two analogues, BMS-340280 and BMS-340278, demonstrated moderate inhibition against hTopo II and cytotoxicity in the cellular assay. BMS-284756 demonstrated greater Gram-positive antibacterial activity and similar inhibition of targets compared with other fluoroquinolones, and more favourable selectivity compared with the other BMS-284756 analogues.

Selective adenosine A 2A receptor antagonists

In the early 1990s it became clear that the A 2A adenosine receptor had characteristics that made it distinct from the other A 1, A 2B and A 3 adenosine receptors. Great progress has been made with the discovery of selective A 2A receptor antagonists. A variety of synthetic substitutions on the xanthine moiety led the chemists of Kyowa–Hakko to discover that introduction of the styryl group in the 8 position of xanthines was critical in achieving compounds endowed with selective A 2A receptor antagonistic properties. One compound, KW 6002, ( E)1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine, is currently being developed for treatment of Parkinson's disease. A number of non-xanthine heterocycles have also been synthesized starting from the non-selective adenosine antagonist CGS 15943, a triazoloquinazoline. Thus, replacement of the phenyl ring of CGS 15943 with a heterocyclic ring such as pyrazole or imidazole, led to a series of interesting compounds whose prototype, SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo[4,3- e]-1,2,4-triazolo[1,5- c]pyrimidine, has become a reference A 2A receptor antagonist. Modification of N7 substituents has progressed to optimize A 2A receptor selectivity and pharmacokinetic characteristics. A related class of compounds having a bicyclic instead of the tricyclic ring structure is also of interest. The prototype of these triazintriazolo derivatives, ZM 241385, is a potent A 2A receptor antagonist; however, it also shows interactions with A 2B receptors. The relevance of the A 2A receptors in specific disease states, especially in the central nervous system, makes this class of adenosine receptor blockers of interest for treatment of neurodegenerative disorders such as Parkinson's disease.

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Intercalative Binding of Small Molecules to Nucleic Acids

The interactions of small molecules with nucleic acids have provoked considerable interest in the field of anticancer drug design over the past three decades; however, critical information linking the physical-chemical properties associated with these complexes with their biological effectiveness remains unclear. Significant progress has been made towards unraveling the structural and dynamic properties of many ligand-DNA complexes which has provided pivotal insight into the design and development of more effective second and third generation chemotherapeutic agents for the successful treatment of many types of cancer. Interactions of ligands with DNA are studied by a variety of physical and biochemical methods in an effort to determine the chemical and physical basis of novel binding phenomena such as DNA base sequence selectivity, correlation of structure-activity relationships, linkages between the geometry and thermodynamic properties describing drug-DNA complexes, and influences of substituent modifications on the physical, chemical, and biological properties of the drug-DNA complex.

New and improved ‘LEGO’ BLOCK protocols for the direct synthesis of hydrophilic ribbon molecules with acid, ester or peptide functionality

Hydrophilic ribbon molecules are produced directly from the reaction of cyclobutene epoxide BLOCKs with norbornene dipolarophiles or indirectly by chemical modification of substituents in preformed lipophilic ribbon molecules. The formation of di- and tetra-acid chloride epoxides holds the key to the formation of ester, acid and amide BLOCKs which are active in 1,3-dipolar cycloadditions with norbornene dipolarophiles, thereby delivering a wide range of substituents into the ribbon molecules and opening up combinatorial opportunities at each step.

Inhibition of neuronal nitric oxide synthase by 4-amino pteridine derivatives: structure-activity relationship of antagonists of (6R)-5,6,7,8-tetrahydrobiopterin cofactor.

The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibitor. Therefore, we developed a series of novel 4-amino pteridine derivatives, anti-pterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the 6-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.

Synthesis and binding affinities for 5-HT 1A, 5-HT 2A and 5-HT 2C receptors of a series of 1- and 2-(4-arylpiperazinylalkyl)-4-(benzoyl)-1,2,3-triazole derivatives

Anumber of 1- and 2-(4-arylpiperazinylalkyl)-4-(benzoyl)-1,2,3-triazole derivatives (1–4) were prepared in order to obtain compounds with a high affinity and selectivity for 5-HT 1A receptors. 5-HT 1A, 5-HT 2A and 5-HT 2C affinities were determined by radioligand binding experiments and the most active compounds were also tested for binding affinities on dopaminergic D-1, D-2 and adrenergic α 1, α 2 receptors. The modification of aromatic substituents, the length of the alkyl chain and its position on the 4-benzoyl-1,2,3-triazole ring were explored. Most of the considered compounds generally showed moderate to high affinity for the 5-HT 1A receptor binding site. Three derivatives 2c, 3c and 3e bind to 5-HT 1A receptors in the nanomolar range (IC 50 values = 2, 7.2 and 2.6 nM respectively). The most active compound, 2c, presented a high degree of selectivity versus all considered receptors. It was found that the benzoyltriazole derivatives 1h and 4c are new selective ligands for 5-HT 2A (IC 50 = 89 nM) and 5-HT 2C receptors (IC 50 = 17 nM), respectively.

Synthesis and evaluation of hapalosin and analogs as MDR-reversing agents

The marine natural product hapalosin and 22 analogs, which incorporated systematic substituent deletions or variations, were prepared. These compounds were evaluated in a cell-based assay for both MDR-reversing activity and general cytotoxicity. Some substituent modifications resulted in lower cytotoxicities, but most structural changes were either detrimental to or did not seriously alter the MDR-reversing activity.

Oxidation of 2,4,6-trichlorophenol catalyzed by iron phthalocyanines covalently bound to silica

Abstract The covalent attachment of an iron phthalocyanine with chlorosulfonyl substituents (FePcSO 2 Cl) onto a functionalized 3-aminopropyl-silica has been achieved. This supported catalyst FePcSO 2 Cl-silica is able to degrade a recalcitrant pollutant like 2,4,6-trichlorophenol (TCP) with hydrogen peroxide as oxidant. In order to improve the catalytic efficiency of the grafted iron phthalocyanine complex, modifications of the macrocycle substituents, passivation of the silica surface, variation of the loading of the carrier and addition of an organic cosolvent to the reaction mixture were carried out.

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action.

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.

Carboxy-substituted cinnamides: a novel series of potent, orally active LTB4 receptor antagonists.

A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.

Conformation and Relative Configuration of a Very Potent Glycosylphosphatidylinositol-Anchoring Inhibitor with an Unusual Tricarbocyclic Sesterterpenoidδ-Lactone Skeleton from the FungusPaecilomyces inflatus

In the course of our screening for glycosylphosphatidylinositol (GPI) inhibitors, we found a fungal strain, Paecilomyces inflatus, which inhibited GPI anchoring in yeast. Bioassay-guided fractionation with gel filtration, MPLC on normal phase and prep. HPLC on reversed-phase yielded a minor secondary metabolite, the substituted hexadecahydroindeno[5′,6′:4,5]cycloocta[1,2-c]pyranyl heptanoate 1, that inhibited GPI synthesis in vitro by yeast microsomes with a MIC of 3.4 nm. Ester 1 specifically inhibited GPI synthesis in eukaryotic, including mammalian cells, but had no significant activity in protozoa. Based on spectroscopic evidence, including UV, FT-IR, FAB-MS, ESI-HR-MS, 1H-NMR, 13C-NMR, DQ-COSY, ROESY, HSQC, and HMBC data, the metabolite 1 was shown to have an unusual tricarbocyclic sesterterpenoid δ-lactone skeleton. Its solution conformation and relative configuration was elucidated with 1H,1H coupling constants and detailed analysis of its ROESY data, coupled with inspection of Dreiding models. In the preliminary investigations on structure-activity relationships, the three derivatives 2 – 4 of ester 1 were prepared by acetylation, catalytic hydrogenation, and intramolecular alkene addition of a hydroxy group, respectively. The test results revealed that the modifications of substituents at the δ-lactone ring or of the C=C bonds of 1 caused a loss of activity by a factor of ca. 500 to 5000. Therefore, it seems that the δ-lactone ring and the C=C bonds in 1 are essential for the potent GPI-inhibitory activity.