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Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antitubercular drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-d-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ-reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement with different electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for most active antimycobacterial compounds by enzymatic inhibition assays and peptide fragment analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Nitrobenzothiazinones (BTZs) are potent active substances against Mycobacterium tuberculosis with currently two investigational drugs in clinical development for the treatment of tuberculosis. BTZs are the first examples for which a metabolic pathway towards transient hydride Meisenheimer complexes (HMC) has been shown in mammals, including humans. In this study, lead optimization efforts on BTZs are guided by the systematic evaluation of the HMC formation propensity combined with multiparameter assessment. For this purpose, a novel cell-based assay was specifically developed and fully implemented, and a library of 5- and 7-substituted BTZs was prepared to study substituent effects on the HMC formation. The multiparameter optimization revealed 5-methylated BTZs as the most preferred scaffolds, demonstrating a reduced HMC formation propensity combined with potent activity and good microsomal stability in vitro. In vivo experiments showed good systemic exposure upon oral administration and efficacy in a murine M. tuberculosis infection model. This study reports a qualified in vitro HMC assay, which not only enabled the selection of next-generation BTZs with improved pharmacokinetic properties but also allowed forecasting their in vivo metabolism., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Florian Kloss has patent #PCT/EP2017/073935 issued to Leibniz-HKI. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ 1 receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the "left" five-membered ring and various amino groups on the "right" side; (2) benzylamino or analogous amino moieties on the "right" side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn - 4a showed the highest σ 1 affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ 1 affinity ( K i = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the "left" hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ 1 affinity. As shown for the propellanamine 18 , removal of the carbamate moiety increased the σ 1 affinity of 9a = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes K i = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti - 5 and 9a as well as propellane 18 adopt binding poses at the σ 1 receptor, which result in energetic values correlating well with their different σ 1 affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti - 5 with the σ 1 receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N -benzyl moiety within the σ 1 receptor-binding pocket, which explains the higher σ 1 affinity of the unsubstituted azapropellane 9a .

Aims: Haloperidol is a neuroleptic drug with high affinity towards the σ 1 receptor (σ 1 R), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N‑(1‑benzylpiperidin‑4-yl)‑4‑fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain)., Main Methods: LMH-2 was designed as haloperidol analog. Its structure was characterized by spectroscopic ( 1 H and 13 C NMR) and spectrometric mass (electronic impact) techniques. Additionally, in silico predictions of pharmacokinetic, pharmacodynamic and toxicological properties were obtained, with promising results. A competitive binding assay using radioligands was employed to evaluate the in vitro affinity for σ 1 R, whereas in vivo antihyperalgesic and antiallodynic activities were investigated using Wistar rats with CCI., Key Findings: LMH-2 showed high affinity for σ 1 R in an in vitro binding assay, with a K i  = 6.0 nM and a high σ 1 R/σ 2 R selectivity ratio. Molecular docking studies were carried out to determine the binding energy and to analyze LMH-2-protein interactions. Through an in silico pharmacological consensus analysis, LMH-2 was considered safe for in vivo evaluation. Thus, LMH-2 had dose-dependent antiallodynic and antihyperalgesic activities; its efficacy was comparable to that of gabapentin, but its potency was 2-times higher than this drug., Significance: LMH-2 administration produced antihyperalgesic and antiallodynic effects by the antagonism of σ 1 R, suggesting its potential use as an analgesic drug for neuropathic pain., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In order to obtain rigid σ 1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH 4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ 1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ 1 affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ 1 affinity, but complete removal of the 12-substituent resulted in the highest σ 1 affinity (K i (4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand-σ 1 receptor complex as does usually the primary hydrophobic region., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Emodin is found in remedies from Traditional Chinese Medicine. Since antihyperglycaemic action was observed in rodents, non-scientific sources advertise emodin intake as a natural cure for diabetes. Emodin was admixed to high fat-food of obese mice at two doses (2 and 5g/kg; daily emodin uptake 103 and 229mg/kg). Comparison was made to ad libitum fed and to food restricted control groups, the latter showing the same weight gain as the corresponding emodin-treated groups. Emodin blunted food intake by 6% and 20% for the low and high dose, which was accompanied by proportionate reductions in weight gain. Emodin reduced blood glucose relative to freely feeding controls, but comparison to weight-matched controls unmasked deterioration, rather than improvement, of basal glycaemia (mmol/l: fed ad libitum, 9.5±0.4; low emodin, 9.4±0.3, weight-matched, 8.2±0.3; high emodin, 7.2±0.4, weight-matched, 6.1±0.3; P<0.01, emodin vs weight-matched) and glucose tolerance (area under the curve, min*mol/l: fed ad libitum, 2.01±0.08; low emodin, 1.97±0.12, weight-matched, 1.75±0.03; high emodin, 1.89±0.07, weight-matched, 1.65±0.05; P<0.0002, emodin vs weight-matched). An insulin tolerance test suggested insulin desensitisation by prolonged emodin treatment. Furthermore, a single oral emodin dose did not affect glucose tolerance in obese mice, whereas intravenous injection in rats suggested a potential of emodin to acutely impair insulin release. Our results show that the antihyperglycaemic action of emodin as well as associated biochemical alterations could be the mere consequences of a spoilt appetite. Published claims of antidiabetic potential via other mechanisms evoke the danger of misuse of natural remedies by diabetic patients., (Copyright © 2017. Published by Elsevier B.V.)

Compound 2-(3,4-dichlorophenoxy)-N-(2-morpholin-4-ylethyl)acetamide (1) was designed, prepared and the in vitro binding evaluation against σ1 and σ2 receptors was measured. Compound 1 showed high σ1 receptor affinity (Ki=42 nM) and it was 36-times more selective for σ1 than σ2 receptor. Also, it was performed a molecular docking of compound 1 into the ligand binding pocket homology model of σ1 receptor, showing a salt bridge between the ionized morpholine ring and Asp126, as well as important short contacts with residues Tyr120, His154 and Trp164. Ligand efficiency indexes and predicted toxicity analysis revealed an excellent intrinsic quality of 1. The antinociceptive effect of compound 1 was determined using the formalin test. The ipsilateral local peripheral (10-300 μg/paw) and intrathecal (100 μg/rat) administration of 1 produced a reduction in formalin-induced nociception. The in vivo results indicated that 1 may be effective in treating inflammatory pain., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti-3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti-3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki=11 μM). However, both propellanamines syn-3 and anti-3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti-3 retain the NMDA antagonistic activity but loose the antiviral activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1) was prepared and the in vitro relative expression of PPARγ, GLUT-4 and PPARα, was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPARγ isoform, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus (NIDDM) rat model. The in vivo results indicated a significant decrease of plasma glucose levels, during the 7 h post-administration. Also, we performed a molecular docking of compound 1 into the ligand binding pocket of PPARγ, showing important short contacts with residues Ser289, His323 and His449 in the active site., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted κ-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine κ pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14. In addition to high κ-opioid receptor affinity they demonstrate high selectivity over μ, δ, σ1, σ2, and NMDA receptors. In the [35S]GTPγS assay full agonism was observed. Because of their high polarity, the secondary amines 14a (log D7.4=0.26) and 14b (log D7.4=0.21) did not penetrate an artificial blood-brain barrier. 14b was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED50=2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located κ receptors, since 14b did not affect centrally mediated referred allodynia and hyperalgesia.

A series of novel diastereoisomeric σ ligands 3 was designed, synthesized and pharmacologically evaluated. The highly rigid [4.3.3]propellane scaffold was used to fix the three dimensional orientation of the pharmacophoric moieties required for σ affinity. The syn,syn-configured aminocarbamate syn,syn-3a reveals the most promising σ₁ affinity (Ki = 77 nM) and selectivity over the σ₂ subtype (21-fold). The σ₂ affinity of all four diastereomers 3 was in the low micromolar range. Analysis of the distance between the hydrophobic regions (phenyl moieties) of the diastereomers 3 led to the longest range of distances (10.3-15.2 Å) for the most potent σ₁ ligand syn,syn-3a, which is in good agreement with pharmacophore models., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Two new series of imidazole derivatives (acetamides: 1-8 and sulfonamides: 9-15) were synthesized using a short synthetic route. Compound 1 as well as the intermediate 16g were characterized by X-ray crystallography. Imidazole derivatives 1-15 were tested in vitro against three unicellular parasites (Giardia intestinalis, Trichomonas vaginalis and Entamoeba histolytica) in comparison with benznidazole (Bzn) and metronidazole. Compound 1 [N-benzyl-2-(2-methyl-4-nitro-1H-imidazol-1-yl)acetamide] was 2 times more active than Bzn against T. vaginalis and G. intestinalis and it was as active as Bzn against E. histolytica. Sulfonamides showed selective toxicity against E. histolytica over the other parasites. Toxicity assay showed that all compounds are non-cytotoxic against MDCK cell line. The results revealed that compounds 1-15 have antiparasitic bioactivity in the micromolar range against the parasites tested, and could be considered as benznidazole bioisosteres.

The title compound, C(10)H(11)NO(5), is of inter-est with respect to its anti-dyslipidemic activity. It was prepared by reaction of 4-nitro-phenol with ethyl 2-bromo-2-methyl-propionate followed by ethyl ester hydrolysis. In the crystal, mol-ecules are linked into centrosymmetric dimers by inter-molecular O-H⋯O hydrogen bonds and the dimers are connected into chains by weak C-H⋯O inter-actions. The packing is further stabilized by offset π-π inter-actions between adjacent benzene rings with a centroid-centroid distance of 3.8643 (17) Å.

A series of ten novel hybrids from benzimidazole and pentamidine were prepared using a short synthetic route. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei, in comparison with pentamidine and metronidazole. Some analogues showed high bioactivity in the low micromolar range (IC(50)<1 microM) against the first four protozoa, which make them significantly more potent than either standard. 1,5-bis[4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy]pentane (2) was 3- and 9-fold more potent againstG. lamblia than metronidazole and pentamidine, respectively. This compound was 23-, 108-, and 13-fold more active than pentamidine against T. vaginalis, E. histolytica and L. mexicana, respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these hybrids should provide new leads against protozoal diseases.