Structure-activity relationship of 4-azaindole-2-piperidine derivatives as agents against Trypanosoma cruzi.

The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline's recently disclosed open-resource "Chagas box" and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery.

2,3,8-Trisubstituted Quinolines with Antimalarial Activity.

Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.

Total Synthesis of (-)-Marinisporolide C.

The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.

Nhatrangin A: Total Syntheses of the Proposed Structure and Six of Its Diastereoisomers.

A total synthesis of the proposed structure of nhatrangin A is described. This strategy relies on two aldol reactions to install the chiral centers at C3/C4 and C3'/C4', a lithium-mediated coupling between an advanced intermediate alkyne and a Weinreb amide to complete the C1-C13 alkyl scaffold, and a Yamaguchi esterification to set the side chain. Discrepancies in the spectroscopic data between synthetic and natural nhatrangins led us to synthesize six more diastereoisomers of the proposed structure of nhatrangin A.

The total synthesis of calcium atorvastatin.

A practical and convergent asymmetric route to calcium atorvastatin (1) is reported. The synthesis of calcium atorvastatin (1) was performed using the remote 1,5-anti asymmetric induction in the boron-mediated aldol reaction of ß-alkoxy methylketone (4) with pyrrolic aldehyde (3) as a key step. Calcium atorvastatin was obtained from aldehyde (3) after 6 steps, with a 41% overall yield.

(1)H chemical shift differences of Prelog-Djerassi lactone derivatives: DFT and NMR conformational studies.

This work reports an experimental and theoretical study of the conformational preferences of several Prelog-Djerassi lactone derivatives, to elucidate the (1)H NMR chemical shift differences in the lactonic core that are associated with the relative stereochemistry of these derivatives. The boat-like conformation of explains the anomalous (1)H chemical shift between H-5a and H-5b, in which the two methyl groups (C-8 and C-9) face H-5b, leading to its higher shielding effect.

Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1-9 displayed good potency (EC50T. cruzi amastigote <1 µM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32-64 µM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.

Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors.

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 µM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.

Total synthesis of (-)-goniotrionin.

A stereoselective total synthesis of the reported structure of goniotrionin (4) has been accomplished. The key steps involved the opening of a chiral epoxide, a highly diastereoselective Mukaiyama aerobic oxidative cyclization, a selective 1,2-syn Mukaiyama aldol reaction, and a Noyori reduction.

1,5-Stereoinduction in boron-mediated aldol reactions of ß,δ-bisalkoxy methylketones containing cyclic protecting groups.

A study of the aldol reactions of boron enolates from methylketones that are protected with dimethylacetonide or di-tert-butylsilyl groups and that possess a trans or cis relationship between the chiral centers is presented. The main objective of this work was to evaluate the influence of the relative stereochemistry between the chiral centers and the steric and electronic influences of the cyclic protecting groups on the aldol reactions. The aldol adducts were obtained with moderate to high 1,5-anti stereoselectivity that was dependent on both the identity of the protecting group on the ß,δ-oxygen stereocenters and the relative stereochemistry between the ß and δ chiral centers. A theoretical analysis of the transition states involving these aldol reactions was performed utilizing DFT (density functional theory).

The role of ß-bulky substituents in aldol reactions of boron enolates of methylketones with aldehydes: experimental and theoretical studies by DFT analysis.

In this work, we show the influence of the volume of the ß-substituents on the levels of 1,5-stereoselectivities of aldol reactions of boron enolates generated from ß-alkoxy methylketones with aldehydes. Excellent levels of 1,5-syn stereoinduction were obtained when the ß-protecting group is a silicon ether. This remarkable selectivity is attributed to the volume of the ß-bulky substituent of the corresponding boron enolate. We have investigated a stereochemical model using DFT analysis to rationalize the sense of 1,5-syn stereoselectivities of ß-alkyl-ß-alkoxy methylketones.

Chagas Disease Drug Discovery in Latin America-A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021.

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing.

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics.

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite's life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.

A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series.

Total synthesis of pteridic acids A and B.

The total synthesis of pteridic acids A and B is reported. The convergent asymmetric synthesis involved the use of a diastereoselective ethyl ketone aldol reaction followed by an efficient spiroketalization and provided pteridic acids A and B in 2.9% and 2.8% overall yield, respectively.

Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity.

Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 µM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 µM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 µM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.

Benzimidazole inhibitors of the major cysteine protease of Trypanosoma brucei.

Aim: Limitations in available therapies for trypanosomiases indicate the need for improved medicines. Cysteine proteases cruzain and rhodesain are validated targets for treatment of Chagas disease and human African trypanosomiasis. Previous studies reported a benzimidazole series as potent cruzain inhibitors. Results & methodology: Considering the high similarity between these proteases, we evaluated 40 benzimidazoles against rhodesain. We describe their structure-activity relationships (SAR), revealing trends similar to those observed for cruzain and features that lead to enzyme selectivity. This series comprises noncovalent competitive inhibitors (best Ki = 0.21 µM against rhodesain) and micromolar activity against Trypanosoma brucei brucei. A cheminformatics analysis confirms scaffold novelty, and the inhibitors described have favorable predicted physicochemical properties. Conclusion: Our results support this series as a starting point for new human African trypanosomiasis medicines.

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-alkoxy methylketones.

Good levels of substrate-controlled, 1,5- syn-stereoinduction are obtained in boron-mediated aldol reactions of beta-trichloromethyl-beta-alkoxy and beta-trifluoromethyl-beta-alkoxy methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group (TBS or PMB). In the case of boron aldol reactions of beta-aryl-beta-alkoxy methylketones, the 1,5- anti-adducts were obtained with high levels of diastereoselectivity only with a beta-OPMB group.

The influence of a beta-electron withdrawing substituent in aldol reactions of methylketone boron enolates.

We wish to describe here that good levels of substrate-based, 1,5-syn-stereocontrol could be achieved in the boron-mediated aldol reactions of beta-trichloromethyl methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group.

Molecular modeling and structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors.

AIM: Chagas disease is endemic in Latin America and no effective treatment is available. Efforts in drug research have focused on several enzymes from Trypanosoma cruzi, among which cruzain is a validated pharmacological target. METHODOLOGY: Chemometric analyses were performed on the data set using the hologram quantitative structure-activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods. Docking simulations were executed using the crystallographic structure of cruzain in complex with a benzimidazole inhibitor. The top-scoring enzyme-inhibitor complexes were selected for the development of the 3D quantitative structure-activity relationship (QSAR) models and to assess the inhibitor binding modes and intermolecular interactions. RESULTS: Benzimidazole derivatives as cruzain inhibitors were used in molecular docking and QSAR studies. Significant statistical indicators were obtained, and the best models demonstrated high predictive ability for an external test set (r 2pred = 0.65, 0.94 and 0.82 for hologram QSAR, comparative molecular field analysis and comparative molecular similarity index analysis, respectively). Additionally, the graphical information of the chemometric analyses demonstrated substantial complementarity with the enzyme-binding site. CONCLUSION: These results demonstrate the relevance of the QSAR models to guide the design of structurally related benzimidazole derivatives with improved potency.