Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity

Chenna, Balachandra; Li, Linfeng; Mellott, Drake M.; Zhai, Xiang; Siqueira-Neto, Jair L.; Bernatchez, Jean A.; Desormeaux, Emily; Hernandez, Elizabeth A; Gomez, Jana; McKerrow, James H.; Cruz‐Reyes, Jorge; Meek, Thomas D.

doi:10.1021/acs.jmedchem.9b02078

Cited by 21 publications

(24 citation statements)

References 62 publications

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“…22 Reaction time: 1 h; obtained as a colorless oil (113 mg, 98% 4-(Chloromethyl)pyridine (2p′). 70 Reaction time: 1 h; Yield: 62%. 5-Chloropent-1-yne (2q′).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Thiourea-Mediated Halogenation of Alcohols

et al. 2020

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The halogenation of alcohols under mild conditions expedited by the presence of substoichiometric amounts of thiourea additives is presented. The amount of thiourea added dictates the pathway of the reaction, which may diverge from the desired halogenation reaction toward oxidation of the alcohol, in the absence of thiourea, or toward starting material recovery when excess thiourea is used. Both bromination and chlorination were highly efficient for primary, secondary, tertiary, and benzyl alcohols and tolerate a broad range of functional groups. Detailed electron paramagnetic resonance (EPR) studies, isotopic labeling, and other control experiments suggest a radical-based mechanism. The fact that the reaction is carried out at ambient conditions, uses ubiquitous and inexpensive reagents, boasts a wide scope, and can be made highly atom economic, makes this new methodology a very appealing option for this archetypical organic reaction.

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“…22 Reaction time: 1 h; obtained as a colorless oil (113 mg, 98% 4-(Chloromethyl)pyridine (2p′). 70 Reaction time: 1 h; Yield: 62%. 5-Chloropent-1-yne (2q′).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Thiourea-Mediated Halogenation of Alcohols

et al. 2020

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“…The enzyme is vital for the parasite physiological processes such as cell replication, nutrition, the invasion of host cells, and the evasion of the host immune system [ 11 , 12 ]. Following these findings, multiple classes of inhibitors, including imidazoles, benzimidazoles, cyclic imides, and vinyl heterocycles, among others, have been designed as cruzain inhibitors [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors

et al. 2021

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Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure–activity relationships (QSARs) were generated along with the investigation of enzyme–inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r2pred = 0.80) and AutoQSAR (q2 = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r2pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors.

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“…12 , 22 The functional groups of the subsets divided by the chemical family resemble those in the previously reported local models shown in Table 1 . Moreover, current efforts in the search for cruzain inhibitors focus on the design and optimization of particular chemotypes, including imidazoles and benzimidazoles, 9 , 86 , 87 N -acyldhydrazones, 88 imides, 89 vinyl peptidomimetics, 2 , 11 , 90 oxadiazoles, 2 , 11 , 91 and triazoles, 10 among others. Molecules that belong to these chemical groups are part of our curated modeling database.…”

Section: Resultsmentioning

confidence: 99%

Predictive Global Models of Cruzain Inhibitors with Large Chemical Coverage

et al. 2021

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Chagas disease affects 8–11 million people worldwide, most of them living in Latin America. Moreover, migratory phenomena have spread the infection beyond endemic areas. Efforts for the development of new pharmacological therapies are paramount as the pharmacological profile of the two marketed drugs currently available, nifurtimox and benznidazole, needs to be improved. Cruzain, a parasitic cysteine protease, is one of the most attractive biological targets due to its roles in parasite survival and immune evasion. In this work, we compiled and curated a database of diverse cruzain inhibitors previously reported in the literature. From this data set, quantitative structure–activity relationship (QSAR) models for the prediction of their pIC 50 values were generated using k -nearest neighbors and random forest algorithms. Local and global models were calculated and compared. The statistical parameters for internal and external validation indicate a significant predictability, with q loo 2 values around 0.66 and 0.61 and external R 2 coefficients of 0.725 and 0.766. The applicability domain is quantitatively defined, according to QSAR good practices, using the leverage and similarity methods. The models described in this work are readily available in a Python script for the discovery of novel cruzain inhibitors.

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Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity

Cited by 21 publications

References 62 publications

Thiourea-Mediated Halogenation of Alcohols

Thiourea-Mediated Halogenation of Alcohols

Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors

Predictive Global Models of Cruzain Inhibitors with Large Chemical Coverage

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