29739-46-6Relevant academic research and scientific papers
Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones
Clark, Robert D.,Morris, Denise N.,Chinigo, Gary,Lawless, Michael S.,Prudhomme, Jacques,Le Roch, Karine G.,Lafuente, Maria José,Ferrer, Santiago,Gamo, Francisco Javier,Gadwood, Robert,Woltosz, Walter S.
, p. 1117 - 1132 (2020)
There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure–activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24–48?h before PfDHODH inhibition would be expected to do so.
The molecular structure of 1,1-dicyanocyclopentane from gas electron diffraction data and ab initio calculations
Dakkouri, Marwan,Typke, Volker
, p. 181 - 197 (2002)
The molecular structure of 1,1-dicyanocyclopentane (DCCP) has been investigated by means of gas-phase electron diffraction and ab initio calculation. Although the electron diffraction data could be fairly good reproduced by a Cs (envelope) model we found it more pertinent to apply a pseudorotation model to account for the dynamic and large amplitude motion in DCCP. Based on this model we analyzed the dependency of the ring geometric parameters and vibrational mean amplitudes on the phase angle φ. For a better elucidation of this distinct dependency we developed particular equations which describe the dependency of the distribution of the delocalized net charges throughout the ring on the phase angle φ. For the purpose of a more systematical study of the substituent effect exerted by the cyano group we also investigated the structure and conformational stability of monocyanocyclopentane (MCCP) by means of various quantum mechanical methods. The MP2 method in combination with the basis sets 6-311 + G(2df,2pd), 6-311 + G(d,p), and 6-31 G(d,p) favors the axial conformer which is in contradiction to earlier results which were obtained from electron diffraction data [J. Mol. Struct., 116 (1984) 29]. Using the same basis sets but the DFT/B3PW91 method, however, leads to a more stable equatorial conformer. This striking behavior is discussed in this paper. The joint electron diffraction and ab initio study has led to the following rα structural parameters of DCCP: r(C≡N) = 1.152(2) A?, r(C42≡) = 1.472(5) A?, average r(C-C)ring = 1.549(3) A?, ∠(C5-Cl-C2) = 103.6(26)°, ∠(NC-C-CN) = 109.0(35)°, ∠(C-C≡N) = 175.2(33)°, and ∠(H-C-H) = 112.7(23)°. The puckering amplitude for the five-membered ring was determined to be q = 0.434(45) A?. The quantum mechanical calculations were carried out by utilizing the Hartree-Fock, density functional B3PW91, and perturbation MP2 methods and applying the basis sets: 6-31 G(d,p), 6-311 G(df,pd), 6-311 + G(d,p) and 6-311 + + (2df,2pd). In contrast to the Mulliken poulation analysis the natural population analysis provided clear evidence for the electronic interaction and bond conjugation within the geminally substituted cyano groups.
Cobalt-bisoxazoline-catalyzed asymmetric kumada cross-coupling of racemic α-bromo esters with aryl grignard reagents
Mao, Jianyou,Liu, Feipeng,Wang, Min,Wu, Lin,Zheng, Bing,Liu, Shangzhong,Zhong, Jiangchun,Bian, Qinghua,Walsh, Patrick J.
supporting information, p. 17662 - 17668 (2015/02/02)
The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.
N′-(Arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT6R) antagonists with unique structural features
Van Loevezijn, Arnold,Venhorst, Jennifer,Iwema Bakker, Wouter I.,De Korte, Cor G.,De Looff, Wouter,Verhoog, Stefan,Van Wees, Jan-Willem,Van Hoeve, Martijn,Van De Woestijne, Rob P.,Van Der Neut, Martina A. W.,Borst, Alice J. M.,Van Dongen, Maria J. P.,De Bruin, Natasja M. W. J.,Keizer, Hiskias G.,Kruse, Chris G.
experimental part, p. 7030 - 7054 (2011/12/15)
The 5-HT6 receptor (5-HT6R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT6R antagonists to improve off-target selectivity compared to basic amine-con
SULFONYLPYRAZOLE AND SULFONYLPYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS
-
Page/Page column 22, (2008/06/13)
This invention concerns sulfonylpyrazoline carboxamidine derivatives as antagonists of 5-HT6 receptors, to methods for the preparation of these compounds and to novel intermediates useful for their synthesis. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes. The compounds have the general formula (1), wherein the symbols have the meanings given in the description.
Heterocyclic-substituted alkylamide acat inhibitors
-
Example 29, (2010/11/29)
Pharmaceutically useful compounds having ACAT inhibitory activity of the formula wherein n is 0, 1, or 2, for X other than tetrazole and n = 2 then R2 = R3 = H; R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, a heteroaromatic group or a hydrocarbon group having from one to 18 carbon atoms; R2 and R3 are hydrogen, halo, hydroxy, alkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl, a heteroaryl, or form a spiroalkyl group; x is a 5-membered heteromonocyclic group containing at least one to four heteroatoms selected from the group consisting of isothiazole, oxazole, thiazole, imidazole, furan, thiophene, pyrrole, tetrazole, 1,2,3-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, and 1,2,4-oxadiazole said heteromonocyclic group being unsubstituted or substituted at any available position along the ring,
Isoxazolyl-substituted alkyl amide ACAT inhibitors
-
, (2008/06/13)
Pharmaceutically useful compounds having ACAT inhibitory activity of the formula STR1 wherein n is 0, 1, or 2, for X other than tetrazole and n=2 then R2 =R3 =H; R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, a heteroaromatic group or a hydrocarbon group having from one to 18 carbon atoms; R2 and R3 are hydrogen, halo, hydroxy, alkyl, alkenyl, cycloalkyl, phenyl, substituted phenyl, a heteroaryl, or form a spiroalkyl group; X is a heteromonocyclic 5-membered ring containing one to four heteroatoms, said heteroatoms being nitrogen, oxygen or sulfur, and combination thereof; and R4 is a hydrocarbon group having from one to 20 carbon atoms are described as well as methods of their manufacture.
SYNTHESIS OF CYCLOPENTANE DERIVATIVES IN THE CATHODIC ELECTROLYSIS OF COMPOUNDS WITH AN ACTIVATED METHYLENE GROUP IN THE PRESENCE OF 1,4-DIBROMOBUTANE
Tatarinova, V. I.,Vasil'ev, A. A.,Petrosyan, V. A.
, p. 2399 - 2401 (2007/10/02)
The cathodic electrolysis of compounds with an activated methylene group in the presence of 1,4-dibromobutane leads to 1,1-disubstituted cyclopentanes.
