James W. McFarland

Estimating the water solubilities of crystalline compounds from their chemical structures alone.

Partial atomic charges are significant descriptors in predicting the water solubilities of crystalline organic compounds from their chemical structures. Lipophilicity remains the predominant factor. It was also found that quantitative estimates of hydrogen bond strengths (hydrogen bond factors) play important roles. These descriptors can be easily interpreted to guide chemists to the synthesis of compounds with increased or decreased water solubility. This work is based on a set of 22 compounds the aqueous solubilities of which were determined by a new potentiometric method, pSOL, and were confirmed, in part, by the traditional shake-flask method. A new software package, HYBOTPLUS, furnished the partial atomic charges and hydrogen bond factors.

A Novel Approach for Prediction of Intestinal Absorption of Drugs in Humans based on Hydrogen Bond Descriptors and Structural Similarity

A new approach to predict the intestinal absorption of drugs in humans is presented. It is based on structural similarity and hydrogen bonding properties (ΣC values) of drug-like compounds. The relationship between gastrointestinal absorption in humans and hydrogen bond descriptors for 100 structurally diverse drugs was studied. From the sigmoid relationship for passively transported drugs it could be concluded that those with ΣC values less than 14 were completely absorbed, whereas those with ΣC values higher than 18 were poorly absorbed. In cases where other transport mechanisms prevail due to special structural features, an absorption threshold can be significantly different. So, instead of including the whole set of compounds in the QSAR analyses, small subsets of 1 to 5 structurally related drugs (nearest neighbors of a drug of interest) estimated by means of similarity calculations were considered. The contribution of the passive transport component and the corresponding influence of hydrogen bond factors on absorption was assumed to be similar within the postulated subsets.

Hydrogen Bond Contributions to Properties and Activities of Chemicals and Drugs

Hydrogen bonding plays an important role in many chemical and biological processes, but this interaction is complex and has been difficult to quantify in correlation analysis. One of the better ways to describe hydrogen bonding strength is to use the thermodynamic parameters of H-bond formation: free energy (ΔG), enthalpy (ΔH), entropy (ΔS) and H-bond binding constant (K). These are connected to each other by the following relationships:

The Chemotherapy of Intestinal Nematodes

\Delta G = - RTln K = \Delta H - T\Delta S

Synthesis of 1,2,4-triazine-(2H,4H)-3,5,-dione anticoccidial agents via palladium-catalyzed cross-coupling reactions

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Further investigation of anticoccidial activity of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine.

It is not difficult to find a novel compound possessing biological activity, but the discovery of a compound with sufficient potency to be considered for introduction to medical practice is a much rarer event. Nevertheless, weakly active compounds are valuable in that their chemical structures may be modified as a means to discover more potent congeners. One of the more common modifications employed is the addition of substituent groups at various positions of an aromatic system. Physical organic chemists have long appreciated the large effects that substituents can have upon the rate and equilibrium constants of organic reactions; in a like manner medicinal chemists have long recognized the often dramatic changes in potency that accompany substitution. The basic problem then is to discover which substituents produce the most advantageous effects in the biological profile of a series. Normally, the purpose of the substituent is to alter the physicochemical characterstics of the parent system; it is these changes that are associated with the altered biological response.

Hydrogen Bond Acceptor and Donor Factors, Ca and Cd: New QSAR Descriptors

In spite of the widespread incidence of intestinal nematodes and the concomitant detrimental effect upon human well-being, the chemotherapy of these parasites remained surprisingly backward until the beginning of the past decade. Even though the 1960s witnessed great advances in the treatment of nematodiasis, there are still only poor remedies for several important worm infestations. The present chapter will attempt to record the progress made in the chemotherapy of intestinal nematodes since the subject was last reviewed in this series [23]. A number of other review articles have appeared since 1959, and some of the more informative and readily available ones are given in references [1–23].

Parabolic relation between drug potency and hydrophobicity

Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among alpha 2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional alpha 2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, alpha 1 agonists and alpha antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate alpha 2 adrenoceptor. alpha 2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.