Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme
4
consisted of seven steps, and was ...highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile
8
. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl
3
of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate
8
, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate
8
. However, the key step of monofluorination at the pyrazine C6 position of intermediate
19
or
22
was not achieved.
Building an efficient and reliable small target motion detection visual system is challenging for artificial intelligence robotics because a small target only occupies few pixels and hardly displays ...visual features in images. Biological visual systems that have evolved over millions of years could be ideal templates for designing artificial visual systems. Insects benefit from a class of specialized neurons, called small target motion detectors (STMDs), which endow them with an excellent ability to detect small moving targets against a cluttered dynamic environment. Some bio-inspired models featured in feed-forward information processing architectures have been proposed to imitate the functions of the STMD neurons. However, feedback, a crucial mechanism for visual system regulation, has not been investigated deeply in the STMD-based neural circuits and its roles in small target motion detection remain unclear. In this paper, we propose a time-delay feedback STMD model for small target motion detection in complex backgrounds. The main contributions of this study are as follows. First, a feedback pathway is designed by transmitting information from output-layer neurons to lower-layer interneurons in the STMD pathway and the role of the feedback is analyzed from the view of mathematical analysis. Second, to estimate the feedback constant, the existence and uniqueness of solutions for nonlinear dynamical systems formed by feedback loop are analyzed
via
Schauder's fixed point theorem and contraction mapping theorem. Finally, an iterative algorithm is designed to solve the nonlinear problem and the performance of the proposed model is tested by experiments. Experimental results demonstrate that the feedback is able to weaken background false positives while maintaining a minor effect on small targets. It outperforms existing STMD-based models regarding the accuracy of fast-moving small target detection in visual clutter. The proposed feedback approach could inspire the relevant modeling of robust motion perception robotics visual systems.
Detecting small moving targets consisting of one or few pixels is technically demanding due to their limited visual features. Motivated by nature, some bio-inspired models have been developed that ...simulate the behavior of small target motion detectors (STMDs), a class of specialized neurons found in insects’ visual neural systems dominating in detecting small moving targets during activities such as predation or courtship. However, the existing models’ high dependence on the sampling frequency of input videos becomes a bottleneck that seriously hinders their real-time applications in the physical world. This is because massive computational power is required to capture and process high-sampling-frequency videos. While model detection performance in low-sampling-frequency videos is plagued by significant spatial errors and weak responses. To address these issues, we propose an STMD-based visual neural model with a fractional-order difference operator for small target motion detection. The fractional-order operator captures instantaneous luminance change and integrates it with memory information, where the instantaneous information dominates the integrated signal. The STMD network further separates the rising and falling luminance components, which are aligned in the time domain and then multiplied to predict the location of moving small targets. Due to the rapid response of instantaneous information and the supplement of memory information, the proposed model locates the small moving targets accurately and robustly in low-sampling-frequencies. Numerical experiments show that the proposed model significantly improves the detection performance for low-sampling-frequency videos.
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To explore the application potential of dual prodrug strategies in the development of anti-HCV agents, a variety of sofosbuvir derivatives with modifications at the C4 or N3 position ...of the uracil moiety were designed and synthesized. Some compounds exhibited potent anti-HCV activities, such as 4e and 8a–8c with similar EC50 values (0.20–0.22 μM) comparative to that of sofosbuvir (EC50 = 0.18 μM) in a genotype 1b based replicon Huh-7 cell line. Moreover, 8b displayed a good human plasma stability profile, and was easily metabolized in human liver microsomes expectantly. On the other hand, aiming to discover novel anti-HCV nucleosides, pyrazin-2(1H)-one nucleosides and their phosphoramidate prodrugs were investigated. Several active compounds were discovered, such as 25e (EC50 = 7.3 μM) and S-29b (EC50 = 19.5 μM). This kind of nucleosides were interesting and would open a new avenue for the development of antiviral agents.
In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and ...evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzobthiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine-induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development.
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•A series of N-substituted cyclic imide derivatives was synthesized.•Four compounds were evaluated for activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel.•Compound 3d showed excellent efficacy in animal behavioral studies of schizophrenia.•Compound 3d possessed acceptable pharmacokinetic properties.•Compound 3d was a promising antipsychotic candidate.
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A simple and efficient approach for the synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone through a neighboring group participation mechanism is reported. This compound ...could be a useful precursor for the synthesis of nucleoside antiviral agents.
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In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the ...evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D2, serotonin 5-HT1A and 5-HT2A receptors, but also exhibited low potency for α1A, H1 and 5-HT2C receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain. Furthermore, 7h exhibited more potent antipsychotic-like effect than aripiprazole in behavioral studies. The preliminary results were promising enough for further research around this scaffold.
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In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and ...evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzobthiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido1,2-apyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.
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In the present study, a series of benzamides, endowed with potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential ...antipsychotics. Among them, 3-(4-(4-(6-fluorobenzodisoxazol-3-yl)-piperidin-1-yl)butoxy)-N-methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological binding profiles. They not only presented potent activities for D2, 5-HT1A, and 5-HT2A receptors, but were also endowed with low activities for 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation. In animal models, compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. It thus provides potential candidates for further preclinical studies.
A series of benzamide derivatives possessing potent dopamine D2, serotonin 5‐HT1A, and 5‐HT2A receptor properties were synthesized and evaluated as potential antipsychotics. Among them, ...5‐(4‐(4‐(benzodisothiazol‐3‐yl)piperazin‐1‐yl)butoxy)‐N‐cyclopropyl‐2‐fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D2, 5‐HT1A, and 5‐HT2A receptors, but was also endowed with low to moderate activities for the 5‐HT2C, H1, and M3 receptors, suggesting a low propensity for inducing weight gain or diabetes. In animal models, compound 4k reduced phencyclidine‐induced hyperactivity with a high threshold for catalepsy or muscle relaxation induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, 4k was selected as a candidate for further development.
Among a series of benzamide derivatives, 5‐(4‐(4‐(benzodisothiazol‐3‐yl)piperazin‐1‐yl)butoxy)‐N‐cyclopropyl‐2‐fluorobenzamide (4k) held the best pharmacological profile, by exhibiting balanced activities for the D2, 5‐HT1A, and 5‐HT2A receptors and low to moderate activities for the 5‐HT2C, H1, and M3 receptors.
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