Synthesis and antimalarial effects of 5,6-dichloro-2-[(4-||4-(diethylamino)-i-methylbutyl] amino||-6-methyl-2-pyrirnidinyl)amino] benzimidazole and related benzimidazoles and lH-imidazo[4,5-b] pyridines

A group of fifty-five 2-[(4-11[(dialkylamino)alkyI]amino11-6-methyl-2-pyrimidinyl)amino]-benzimidazoles (VII) was synthesized in 3-88% yield by the condensation of the requisite 2-[(2-benzimidazolyl)amino]-4-chloro-6-methylpyrimidine (VI) with the appropriate polyamine in ethanol-hydrochloric acid or neat with excess amine containing potassium iodide. The 2-[(2-benzimidazolyl)amino]-6-methyl-4-pyrirnidinol precursors (V), obtained in 11-51% yield by cyclization of 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine with a suitably substituted o-phenylenediamine, were chlorinated with phosphorus oxychloride to give the intermediate 2-[(2-benzimidazolyl)amino]-4-chloro-6-rnethylpyrimidines (VI) (27-99%). Oxidation of 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl] amino 11-6-methyl-2-pyrimidinyl) amino ]benzimidazole ( 29 ) with m-chloroperbenzoic acid gave the distal N⁴'-oxide ( 31 ) (19%). Fusion of 2,3-uiaminopyridine with 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine provided 2-[(4-hydroxy-6-tnethyl-2-pyrimidinyl)amino]-lH-imitlazo[4,5-b]pyrimidine (VIII) (30%), which upon chlori-nation with phosphorus oxychloride (63%) followed by amination with i N, N-diethylethylene-diamine afforded 2-(4-11[2-(diethylamino)ethyl] amino 11-6-methyl-2-pyrimidinyl)-lH-imidazo [4,5-b]pyridine (X) (8%). Thirty-eight of the novel 2-[(4-amino-6-methyl-2-pyrimidinyl)amino]-benzimidazoles possessed “curative” activity against Plasmodium berghei at single subcutaneous doses ranging from 20.640 mg./kg. Orally, thirty-one compounds exhibited suppressive activity against P. berghei comparable with or superior to the reference drugs 1-(p-chlorophenyl)-3-(4-11[2-(diethylarnino)ethyl]amino 11-6-methyl-2-pyrimidinyl)guanidine (I) and quinine hydrochloride, while twelve of them were 5 to 28 times as potent as I and quinine hydrochloride. Eight compounds also displayed strong suppressive activity against P. gallinaceum in chicks. 5,6-Dichloro-2-[(4-112-(diethylamino)ethyl]amino11-6-methyl-2-pyrimidinyl] benzimidazole (18) showed marked activity against a cycloguanil-resistant line of P. berghei, and the most promising member of the series, namely 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl]amino11-6-methyl-2-pyrimidinyl)amino]benzimidazole ( 29 ) (Q = 28), was designated for preclinical toxico-logical studies and clinical trial. Structure-activity relationships are discussed.     

Found in the Folds: A Rediscovery of Ancient Egyptian Pleated Textiles and the Analysis of Carbohydrate Coatings

Charles T. Currelly, first director of the Royal Ontario Museum, participated in excavations of the tomb of King Nebhepetre, now known as Mentuhotep II, (Dynasty XI) in Deir el-Bahri, Egypt in 1906. He brought to Canada many objects from the excavations, and objects that he purchased while in Egypt; these formed the initial collection of the museum. Among the objects were seven fragments of fine linen cloth with intricate pleat patterns. Recently, the cloths became the subject of a study to learn how they had retained their pleats for 4000 years. Samples were examined and analysed using polarised light microscopy, scanning electron microscopy-electron dispersive X-ray spectrometry, gas chromatography-mass spectrometry, and pyrolysis-gas chromatography-mass spectrometry. Three of the cloths were likely fragments of clothing re-purposed as bandages and were found to be saturated in mummification balms composed of Pinaceae resin, Pistacia resin, and an essential oil characterised by a high abundance of cedrol, possibly originating from a juniper species. All seven of the cloths were found to have traces of polysaccharides from two probable sources: an arabinogalactan gum such as gum arabic or a fruit gum, and a polyglucoside, possibly starch.     

A simple zero length surface-modification approach for preparing novel bifunctional supports for co-immobilisation studies

A straightforward method of creating a bifunctional support possessing pre-defined ratios of amine and chloromethyl groups based upon a controlled conversion of standard Merrifield resin is presented. It avoids the extensive optimisation of reactant concentrations and reaction conditions required by existing methods. Furthermore, it avoids increases in the spacer/linker length that lead to detrimental reductions in the rigidity of the grafted layer. The method will allow for efficient, predictable and reproducible co-immobilisation of molecular species.     

On the formation mechanism for electrically generated exciplexes in a carbazole–pyridine copolymer

Although carbazole‐containing copolymers are frequently used as hole‐transporting host materials for polymer organic light‐emitting diodes (OLEDs), they often suffer from the formation of undesired exciplexes when the OLED is operated. The reason why exciplexes sometimes form for electrical excitation, yet not for optical excitation is not well understood. Here, we use luminescence measurements and quantum chemical calculations to investigate the mechanism of such exciplex formation for electrical excitation (electroplex formation) in a carbazole–pyridine copolymer. Our results suggest that the exciplex is formed via a positively charged interchain precursor complex. This complex is stabilized by interactions that involve the nitrogen lone pairs on both chain segments. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

Vanishing Fisher Information

There are consistently estimable parameters of interest whose semiparametric Fisher information vanishes at some points of the model in question. Here we investigate how bad this is for estimation.     

When should you sack a football manager? Results from a simple model applied to the English Premiership

What strategy should a football (soccer, in American parlance) club adopt when deciding whether to sack its manager? This paper introduces a simple model assuming that a club's objective is to maximize the number of league points that it scores per season. The club's strategy consists of three choices: the length of the honeymoon period during which it will not consider sacking a new manager, the level of the performance trapdoor below which the manager get the sack, and the weight that it will give to more recent games compared to earlier ones. Some data from the last six seasons of the English Premiership are used to calibrate the model. At this early stage of the research, the best strategy appears to have only a short honeymoon period of eight games (much less than the actual shortest period of 12 games), to set the trapdoor at 0.74 points per game, and to put 47% of the weight on the last five games. A club adopting this strategy would obtain on average 56.8 points per season, compared to a Premiership average of 51.8 points.     

On the bounded version of Hilbert's tenth problem

 The paper establishes lower bounds on the provability of 𝒟=NP and the MRDP theorem in weak fragments of arithmetic. The theory I ⁵ E ₁ is shown to be unable to prove 𝒟=NP. This non-provability result is used to show that I ⁵ E ₁ cannot prove the MRDP theorem. On the other hand it is shown that I ¹ E ₁ proves 𝒟 contains all predicates of the form (∀i≤|b|)P(i,x)^Q(i,x) where ^ is =, <, or ≤, and I ⁰ E ₁ proves 𝒟 contains all predicates of the form (∀i≤b)P(i,x)=Q(i,x). Here P and Q are polynomials. A conjecture is made that 𝒟 contains NLOGTIME. However, it is shown that this conjecture would not be sufficient to imply 𝒟=N P. Weak reductions to equality are then considered as a way of showing 𝒟=NP. It is shown that the bit-wise less than predicate, ≤₂, and equality are both co-NLOGTIME complete under FDLOGTIME reductions. This is used to show that if the FDLOGTIME functions are definable in 𝒟 then 𝒟=N P. Received: 13 July 2001 / Revised version: 9 April 2002 / Published online: 19 December 2002 Key words or phrases: Bounded Arithmetic – Bounded Diophantine Complexity