Research

15 pages, 8974 KiB

Open AccessArticle

Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity

by Ramanjaneyulu Rayala, Prakash Chaudhari, Ashley Bunnell, Bracken Roberts, Debopam Chakrabarti and Adel Nefzi

Int. J. Mol. Sci. 2023, 24(24), 17414; https://doi.org/10.3390/ijms242417414 - 12 Dec 2023

Viewed by 1365

Abstract

Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction [...] Read more.

Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available carboxylic acids, the parallel synthesis of a variety of disubstituted 4-(piperazin-1-ylmethyl)thiazol-2-amine derivatives is described. the screening of the compounds led to the identification of antiplasmodial compounds that exhibited interesting antimalarial activity, primarily against the Plasmodium falciparum chloroquine-resistant Dd2 strain. The hit compound 2291-61 demonstrated an antiplasmodial EC₅₀ of 102 nM in the chloroquine-resistant Dd2 strain and a selectivity of over 140. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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14 pages, 3001 KiB

Open AccessArticle

Low Molecular Weight Inhibitors Targeting the RNA-Binding Protein HuR

by Benjamin Philipp Joseph, Verena Weber, Lisa Knüpfer, Alejandro Giorgetti, Mercedes Alfonso-Prieto, Sybille Krauß, Paolo Carloni and Giulia Rossetti

Int. J. Mol. Sci. 2023, 24(17), 13127; https://doi.org/10.3390/ijms241713127 - 23 Aug 2023

Cited by 1 | Viewed by 1484

Abstract

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to [...] Read more.

The RNA-binding protein human antigen R (HuR) regulates stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. This protein has been progressively recognized as a relevant therapeutic target for several pathologies, like cancer, neurodegeneration, as well as inflammation. Inhibitors of mRNA binding to HuR might thus be beneficial against a variety of diseases. Here, we present the rational identification of structurally novel HuR inhibitors. In particular, by combining chemoinformatic approaches, high-throughput virtual screening, and RNA–protein pulldown assays, we demonstrate that the 4-(2-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)hydrazineyl)benzoate ligand exhibits a dose-dependent HuR inhibition effect in binding experiments. Importantly, the chemical scaffold is new with respect to the currently known HuR inhibitors, opening up a new avenue for the design of pharmaceutical agents targeting this important protein. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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18 pages, 2906 KiB

Open AccessArticle

Mycobacterium tuberculosis Inhibitors Based on Arylated Quinoline Carboxylic Acid Backbones with Anti-Mtb Gyrase Activity

by Mark Tristan J. Quimque, Adrian D. Go, Justin Allen K. Lim, Warren S. Vidar and Allan Patrick G. Macabeo

Int. J. Mol. Sci. 2023, 24(14), 11632; https://doi.org/10.3390/ijms241411632 - 19 Jul 2023

Cited by 2 | Viewed by 1319

Abstract

New antitubercular agents with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new arylated quinoline carboxylic acids (QCAs) having activity against replicating and non-replicating Mycobacterium [...] Read more.

New antitubercular agents with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new arylated quinoline carboxylic acids (QCAs) having activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb), the causative agent of TB. Thus, the synthesis, characterization, and in vitro screening (MABA and LORA) of 48 QCAs modified with alkyl, aryl, alkoxy, halogens, and nitro groups in the quinoline ring led to the discovery of two QCA derivatives, 7i and 7m, adorned with C-2 2-(naphthalen-2-yl)/C-6 1-butyl and C-2 22-(phenanthren-3-yl)/C-6 isopropyl, respectively, as the best Mtb inhibitors. DNA gyrase inhibition was shown to be exhibited by both, with QCA 7m illustrating better activity up to a 1 μM test concentration. Finally, a docking model for both compounds with Mtb DNA gyrase was developed, and it showed a good correlation with in vitro results. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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18 pages, 6172 KiB

Open AccessArticle

Structure-Based Discovery of Receptor Activator of Nuclear Factor-κB Ligand (RANKL)-Induced Osteoclastogenesis Inhibitors

by Vagelis Rinotas, Fotini Liepouri, Maria-Dimitra Ouzouni, Niki Chalkidi, Christos Papaneophytou, Mariza Lampropoulou, Veroniki P. Vidali, George Kontopidis, Elias Couladouros, Elias Eliopoulos, Athanasios Papakyriakou and Eleni Douni

Int. J. Mol. Sci. 2023, 24(14), 11290; https://doi.org/10.3390/ijms241411290 - 10 Jul 2023

Cited by 3 | Viewed by 1006

Abstract

Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising [...] Read more.

Receptor activator of nuclear factor-κB ligand (RANKL) has been actively pursued as a therapeutic target for osteoporosis, given that RANKL is the master mediator of bone resorption as it promotes osteoclast differentiation, activity and survival. We employed a structure-based virtual screening approach comprising two stages of experimental evaluation and identified 11 commercially available compounds that displayed dose-dependent inhibition of osteoclastogenesis. Their inhibitory effects were quantified through TRAP activity at the low micromolar range (IC₅₀ < 5 μΜ), but more importantly, 3 compounds displayed very low toxicity (LC₅₀ > 100 μΜ). We also assessed the potential of an N-(1-aryl-1H-indol-5-yl)aryl-sulfonamide scaffold that was based on the structure of a hit compound, through synthesis of 30 derivatives. Their evaluation revealed 4 additional hits that inhibited osteoclastogenesis at low micromolar concentrations; however, cellular toxicity concerns preclude their further development. Taken together with the structure–activity relationships provided by the hit compounds, our study revealed potent inhibitors of RANKL-induced osteoclastogenesis of high therapeutic index, which bear diverse scaffolds that can be employed in hit-to-lead optimization for the development of therapeutics against osteolytic diseases. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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19 pages, 5246 KiB

Open AccessArticle

Targeting RNA Structure to Inhibit Editing in Trypanosomes

by Francis A. Acquah and Blaine H. M. Mooers

Int. J. Mol. Sci. 2023, 24(12), 10110; https://doi.org/10.3390/ijms241210110 - 14 Jun 2023

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Abstract

Mitochondrial RNA editing in trypanosomes represents an attractive target for developing safer and more efficient drugs for treating infections with trypanosomes because this RNA editing pathway is not found in humans. Other workers have targeted several enzymes in this editing system, but not [...] Read more.

Mitochondrial RNA editing in trypanosomes represents an attractive target for developing safer and more efficient drugs for treating infections with trypanosomes because this RNA editing pathway is not found in humans. Other workers have targeted several enzymes in this editing system, but not the RNA. Here, we target a universal domain of the RNA editing substrate, which is the U-helix formed between the oligo-U tail of the guide RNA and the target mRNA. We selected a part of the U-helix that is rich in G-U wobble base pairs as the target site for the virtual screening of 262,000 compounds. After chemoinformatic filtering of the top 5000 leads, we subjected 50 representative complexes to 50 nanoseconds of molecular dynamics simulations. We identified 15 compounds that retained stable interactions in the deep groove of the U-helix. The microscale thermophoresis binding experiments on these five compounds show low-micromolar to nanomolar binding affinities. The UV melting studies show an increase in the melting temperatures of the U-helix upon binding by each compound. These five compounds can serve as leads for drug development and as research tools to probe the role of the RNA structure in trypanosomal RNA editing. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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32 pages, 22292 KiB

Open AccessArticle

Structure-Based Design and Pharmacophore-Based Virtual Screening of Combinatorial Library of Triclosan Analogues Active against Enoyl-Acyl Carrier Protein Reductase of Plasmodium falciparum with Favourable ADME Profiles

by Cecile Bieri, Akori Esmel, Melalie Keita, Luc Calvin Owono Owono, Brice Dali, Eugene Megnassan, Stanislav Miertus and Vladimir Frecer

Int. J. Mol. Sci. 2023, 24(8), 6916; https://doi.org/10.3390/ijms24086916 - 07 Apr 2023

Cited by 2 | Viewed by 1626

Abstract

Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of [...] Read more.

Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum (PfENR) using computer-aided combinatorial and pharmacophore-based molecular design. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) complexation QSAR model was developed for triclosan-based inhibitors (TCL) and a significant correlation was established between the calculated relative Gibbs free energies of complex formation

(∆ ∆ G_{c o m})

between PfENR and TCL and the observed inhibitory potencies of the enzyme

({I C}_{50}^{e x p})

for a training set of 20 known TCL analogues. Validation of the predictive power of the MM-PBSA QSAR model was carried out with the generation of 3D QSAR pharmacophore (PH4). We obtained a reasonable correlation between the relative Gibbs free energy of complex formation

{∆ ∆ G}_{c o m}

and

{I C}_{50}^{e x p}

values, which explained approximately 95% of the PfENR inhibition data:

{{p I C}_{50}^{e x p} = - 0.0544 \times {∆ ∆ G}_{c o m} + 6.9336, R}^{2} = 0.95

. A similar agreement was established for the PH4 pharmacophore model of the PfENR inhibition (

{p I C}_{50}^{e x p} = 0.9754 \times {p I C}_{50}^{p r e} + 0.1596

,

R^{2} = 0.98

). Analysis of enzyme–inhibitor binding site interactions suggested suitable building blocks to be used in a virtual combinatorial library of 33,480 TCL analogues. Structural information derived from the complexation model and the PH4 pharmacophore guided us through in silico screening of the virtual combinatorial library of TCL analogues to finally identify potential new TCL inhibitors effective at low nanomolar concentrations. Virtual screening of the library by PfENR-PH4 led to a predicted

{I C}_{50}^{p r e}

value for the best inhibitor candidate as low as 1.9 nM. Finally, the stability of PfENR-TCLx complexes and the flexibility of the active conformation of the inhibitor for selected top-ranking TCL analogues were checked with the help of molecular dynamics. This computational study resulted in a set of proposed new potent inhibitors with predicted antimalarial effects and favourable pharmacokinetic profiles that act on a novel pharmacological target, PfENR. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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9 pages, 2709 KiB

Open AccessCommunication

Short, Lipidated Dendrimeric γ-AApeptides as New Antimicrobial Peptidomimetics

by Yafeng Wang, Menglin Xue, Ruixuan Gao, Soumyadeep Chakraborty, Shaohui Wang, Xue Zhao, Meng Gu, Chuanhai Cao, Xingmin Sun and Jianfeng Cai

Int. J. Mol. Sci. 2023, 24(7), 6407; https://doi.org/10.3390/ijms24076407 - 29 Mar 2023

Cited by 1 | Viewed by 1039

Abstract

Antibiotic resistance is one of the most significant issues encountered in global health. There is an urgent demand for the development of a new generation of antibiotic agents combating the emergence of drug resistance. In this article, we reported the design of lipidated [...] Read more.

Antibiotic resistance is one of the most significant issues encountered in global health. There is an urgent demand for the development of a new generation of antibiotic agents combating the emergence of drug resistance. In this article, we reported the design of lipidated dendrimeric γ-AApeptides as a new class of antimicrobial agents. These AApeptides showed excellent potency and broad-spectrum activity against both Gram-positive bacteria and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The mechanistic studies revealed that the dendrimeric AApeptides could kill bacteria rapidly through the permeabilization of bacterial membranes, analogous to host-defense peptides (HDPs). These dendrimers also did not induce antibiotic resistance readily. The easy access to the synthesis, together with their potent and broad-spectrum activity, make these lipidated dendrimeric γ-AApeptides a new generation of antibacterial agents. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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19 pages, 2195 KiB

Open AccessArticle

Sinapic Acid Co-Amorphous Systems with Amino Acids for Improved Solubility and Antioxidant Activity

by Ewa Garbiec, Natalia Rosiak, Ewa Tykarska, Przemysław Zalewski and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2023, 24(6), 5533; https://doi.org/10.3390/ijms24065533 - 14 Mar 2023

Cited by 10 | Viewed by 1494

Abstract

The objective of this study was to obtain co-amorphous systems of poorly soluble sinapic acid using amino acids as co-formers. In order to assess the probability of the interaction of amino acids, namely, arginine, histidine, lysine, tryptophan, and proline, selected as co-formers in [...] Read more.

The objective of this study was to obtain co-amorphous systems of poorly soluble sinapic acid using amino acids as co-formers. In order to assess the probability of the interaction of amino acids, namely, arginine, histidine, lysine, tryptophan, and proline, selected as co-formers in the amorphization of sinapic acid, in silico studies were carried out. Sinapic acid systems with amino acids in a molar ratio of 1:1 and 1:2 were obtained using ball milling, solvent evaporation, and freeze drying techniques. X-ray powder diffraction results confirmed the loss of crystallinity of sinapic acid and lysine, regardless of the amorphization technique used, while remaining co-formers produced mixed results. Fourier-transform infrared spectroscopy analyses revealed that the co-amorphous sinapic acid systems were stabilized through the creation of intermolecular interactions, particularly hydrogen bonds, and the potential formation of salt. Lysine was selected as the most appropriate co-former to obtain co-amorphous systems of sinapic acid, which inhibited the recrystallization of sinapic acid for a period of six weeks in 30 °C and 50 °C. Obtained co-amorphous systems demonstrated an enhancement in dissolution rate over pure sinapic acid. A solubility study revealed a 12.9-fold improvement in sinapic acid solubility after introducing it into the co-amorphous systems. Moreover, a 2.2-fold and 1.3-fold improvement in antioxidant activity of sinapic acid was observed with respect to the ability to neutralize the 2,2-diphenyl-1-picrylhydrazyl radical and to reduce copper ions, respectively. Full article

(This article belongs to the Special Issue Small Molecule Drug Design and Research 2.0)

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