Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreenTM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC50) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.

Binaural neurons in the mustache bat's inferior colliculus. I. Responses of 60-kHz EI units to dichotic sound stimulation

1. Single-unit responses to closed-field, dichotic sound stimuli were obtained from EI neurons in the mustache bat's inferior colliculus; these neurons are excited by sound to the contralateral ear and inhibited by sound to the ipsilateral ear. All units were tuned to the 60-kHz component of the bat's sonar signal. The goal of the study was to describe basic features of the sensitivity to interaural intensity differences (IIDs) and sound intensity among an isofrequency population of EI neurons. The following paper describes how these features of IID sensitivity shape the response to free-field sounds. 2. Three features of IID sensitivity were considered. The inhibitory threshold (Figs. 1 and 2) described the IID at which inhibitory effects became pronounced; it was defined as the IID at which the excitatory response to contralateral sound was suppressed by 50%. Most units (68%) were inhibited at positive IID values, for which the ipsilateral (inhibitory) sound was more intense. The maximum inhibition (Figs. 1 and 3) described the strength of ipsilateral inhibition; it was defined as the percent that each unit was inhibited below its response to monaural stimulation of the contralateral ear. The majority of units (58%) were almost totally suppressed by a sufficiently intense ipsilateral sound. The IID range (Figs. 1 and 4) described the sharpness or slope of the IID cutoff; it was defined as the IID range over which the response changed from nearly unsuppressed (80% of maximum response) to near maximum suppression (20% of maximum response). Most units (71%) had IID ranges of less than or equal to 15 dB. 3. A significant correlation between the inhibitory threshold and the maximum inhibition (Fig. 5) among the sample of EI units suggests that some common neural mechanisms underlie these features of IID sensitivity. 4. The response of EI neurons to binaural stimuli was a function of sound intensity as well as IID (Fig. 7). In part, this resulted from intensity-dependent changes in properties of binaural inhibition. For most units, basic measures of IID sensitivity changed to a limited extent as the sound intensity changed.(ABSTRACT TRUNCATED AT 400 WORDS)

Diel Distribution and Activity of American Eels (Anguilla rostrata) in a Cave-Spring

American eels (Anguilla rostrata) in a Florida cave-spring (total population [Formula: see text] 142 eels, density [Formula: see text] 0.03 eels/m2) showed distinctive day versus night differences in distribution and activity. Larger eels occurred deeper at all times. Eels were diurnally quiescent, nocturnally active, and changed over between behavior modes roughly at dusk and dawn, although considerable variability existed in timing of changeover. Changeover at dusk involved movement from deeper regions of low food to shallower regions of high food concentration, with smaller eels more likely to migrate. Changing light levels apparently determined onset and cessation of activity, with an inhibitory threshold of 10–100 lx influencing movement between deep and shallow regions. An endogenous rhythm and hunger may have also affected activity patterns.

Characteristics of sustained graded inspiratory inhibition by phasic lung volume changes

The dynamic characteristics of graded reversible inspiratory inhibition by vagal feedback were investigated in pentobarbital-anesthetized paralyzed cats, ventilated with a servo respirator. The volume and time associated with various levels of graded inhibition were determined by using a series of constant-flow lung inflations. Protracted phrenic inhibition was produced by lung inflation, which was arrested when the phrenic discharge was partially inhibited. Thereafter, the volume was withdrawn along a trajectory that approximately paralleled the fall in inhibitory threshold. This volume-withdrawal trajectory would be expected to produce a sustained nearly constant level of inhibition based on the results determined from the constant-flow inflations. However, the observed inhibition exceeded that expected, increasing to a maximum and then decreasing to expected values over a period ranging from 1 to 2 s in most animals. This excess inhibition cannot be attributed to the known dynamic properties of pulmonary stretch receptors; their activity should be reduced, for any particular lung volume, during the volume withdrawal maneuver. These results suggest a central integrative processing of vagal afferent activity that causes inhibition to lag volume. This delay acts to promote inspiratory off-switching because it prevents the development of a protracted period of reversible inhibition.

The Effect of Light on the Shadow Reaction of the Sea Urchin, Diadema Setosum (LESKE)

1. The shadow reaction of the spine jerk in Diadema setosum has been studied with an improved optical system and a timing device. 2. Studies on the variation of the inhibitory threshold with time at which light is admitted after cessation of the preceding light, have differentiated two distinct periods. The inhibitory threshold stays constant during the initial period and then rises sharply. The length of the initial period and the rate of rise in the later phase are found to be temperature-dependent, the former being affected, in addition, by the intensity of the preceding light. 3. The reciprocity of area and intensity of light is proved for both the preceding and the inhibitory light. 4. A new approach is made to study the Weber-Fechner law in shadow reactions and it is found that the reaction in D. setosum obeys the law. In connexion with this it is found that a light, sub-threshold for eliciting a reaction, can still be effective in inhibiting it. 5. The mechanism involved is discussed in relation to our earlier ideas (Millott & Yoshida, 1960b).