Pharmacophoric Moieties Research Articles

Contilisant+Tubastatin A Hybrids: Polyfunctionalized Indole Derivatives as New HDAC Inhibitor-Based Multitarget Small Molecules with In Vitro and In Vivo Activity in Neurodegenerative Diseases.

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC50 = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.

Targeted Hybridization: Pyrazine‐2‐Carbohydrazide Derivatives as Promising Antitubercular and Antimicrobial Leads

AbstractIn an attempt to identify a new pharmacological lead which should be more potent than the established drug pyrazinamide, a molecular hybridization technique was applied to fuse two pharmacophore moieties: pyrazine‐2‐carbohydrazide (1) and diphenyl ether/piperazinyl derivative (2), to isolate a new series of hybrid molecules. The synthesized compounds were tested in vitro for their antibacterial and antimycobacterial properties against E. coli and S. aureus and Mycobacterium TB H37Rv strains. In comparison to the reference medication (pyrazinamide) these compounds exhibited moderate antitubercular and antibacterial action, with a MIC value of 15.625–125 µg/mL. All the synthesized molecules were characterized through IR, NMR and mass spectrometry. Docking studies were carried out in order to have better understanding related to protein and ligand receptor interactions.

Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors.

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations.

Nascent pharmacological advancement in adamantane derivatives.

The adamantane moiety has attracted significant attention since its discovery in 1933 due to its remarkable structural, chemical, and medicinal properties. This molecule has a notable impact in the therapeutic field because of its "add-on" lipophilicity to any pharmacophoric moieties. As in the case of molecular hybridization, in which one pharmacophore is attached to another one(s) with a probability of increasing the biological activity, adding an adamantane unit improves the absorption distribution, metabolism and excretion properties of the resultant hybrid molecule. This review summarizes various reports highlighting the biological activities of adamantane-based synthetic compounds and their structure-activity relationship study. The information presented in this review may open up possible dimensions for adamantane-based drug development and discovery in the pharmaceutical industry after proper structural modifications.

Unexpected products using Biginelli reaction: Synthesis, antimicrobial potency, docking simulation, and DFT investigations of some new amidopyridines

The Biginelli reaction of 3-oxo-N-(2-pyridyl)butanamide with thiourea (or urea) and some aromatic aldehydes afforded new chemical skeletons containing tetrahydropyrimidine, pyridine, and carboxamide pharmacophoric moieties. The expected products of this reaction were not isolated in the case of 4-nitrobenzaldehyde, pyridine-2-carbaldehyde, and thiophene-2-carbaldehyde; rather the corresponding acrylamide derivatives were obtained. Chemical structures of the newly synthesized hybrids were elucidated by FT-IR, NMR spectroscopy in addition to mass spectrometry and elemental analyses. The in-vitro antimicrobial activity showed that the products were highly active against the tested pathogens that were confirmed through molecular docking simulation with different proteins such as PDBID:3t88, 2wje, 1tgh, and 4ynt which showed a different binding affinity with attraction of amino acids of proteins. Furthermore, the optimization of different pyridine carboxamides utilized a DFT/B3LYP-6311(G) basis set to know the cyclization of butanamide 1 with thiourea and different aldehydes in the presence of electron-donating/withdrawing groups which affected of the expected products with different transition states. Moreover, the determination of the energy gap and physical descriptors of these pyridine carboxamide derivatives showed the stability of tetrahydropyrimidines 2a,b due to the presence of donating groups which enhanced the activity and stability. Determination of the ESP and MEP of compounds 2a,b confirmed a correlation with biological evaluations.

Design, Synthesis, and Proof of Concept of Balanced Dual Inhibitors of Butyrylcholinesterase (BChE) and Histone Deacetylase 6 (HDAC6) for the Treatment of Alzheimer's Disease.

Concomitant inhibition of butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) is supposed to be effective in the treatment of Alzheimer's disease (AD). Inspired by our previous efforts in designing BChE inhibitors, herein, selective BChE and HDAC6 dual inhibitors were successfully identified through the fusion of the core pharmacophoric moiety of BChE and HDAC6 inhibitors. After the structure-activity relationship (SAR) studies, two compounds (24g and 29a) were confirmed to have superior inhibitory activity against BChE (the IC50 against hBChE are 4.0 and 1.8 nM, respectively) and HDAC6 (the IC50 against HDAC6 are 8.9 and 71.0 nM, respectively). These two compounds showed prominently neuroprotective effects in vitro, potent reactive oxygen species (ROS) scavenging effects, and effective metal ion (Fe2+ and Cu2+) chelation. In addition, they exhibited pronounced inhibition of phosphorylated tau and a moderate immunomodulatory effect, with a lack of neurotoxicity at the cellular level. In vivo studies showed that both 24g and 29a ameliorated the cognitive impairment in an Aβ1-42-induced mouse model at a low dosage (2.5 mg/kg). Our data demonstrated that BChE/HDAC6 dual inhibitors could establish the basis for a potential new symptomatic and disease-modifying strategy to treat AD.

An overview on the antimalarial activity of 1,2,4-trioxanes, 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes.

The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).

Antiplasmodial, Trypanocidal, and Genotoxicity In Vitro Assessment of New Hybrid α,α-Difluorophenylacetamide-statin Derivatives.

Statins present a plethora of pleiotropic effects including anti-inflammatory and antimicrobial responses. A,α-difluorophenylacetamides, analogs of diclofenac, are potent pre-clinical anti-inflammatory non-steroidal drugs. Molecular hybridization based on the combination of pharmacophoric moieties has emerged as a strategy for the development of new candidates aiming to obtain multitarget ligands. Considering the anti-inflammatory activity of phenylacetamides and the potential microbicidal action of statins against obligate intracellular parasites, the objective of this work was to synthesize eight new hybrid compounds of α,α-difluorophenylacetamides with the moiety of statins and assess their phenotypic activity against in vitro models of Plasmodium falciparum and Trypanosoma cruzi infection besides exploring their genotoxicity safety profile. None of the sodium salt compounds presented antiparasitic activity and two acetated compounds displayed mild anti-P. falciparum effect. Against T. cruzi, the acetate halogenated hybrids showed moderate effect against both parasite forms relevant for human infection. Despite the considerable trypanosomicidal activity, the brominated compound revealed a genotoxic profile impairing future in vivo testing. However, the chlorinated derivative was the most promising compound with chemical and biological profitable characteristics, without presenting genotoxicity in vitro, being eligible for further in vivo experiments.

An Artificial Peptide-Based Bifunctional HIV-1 Entry Inhibitor That Interferes with Viral Glycoprotein-41 Six-Helix Bundle Formation and Antagonizes CCR5 on the Host Cell Membrane.

Human immunodeficiency virus type 1 (HIV-1) is characterized by high variability and drug resistance. This has necessitated the development of antivirals with a new chemotype and therapy. We previously identified an artificial peptide with non-native protein sequence, AP3, with the potential to inhibit HIV-1 fusion through targeting hydrophobic grooves on the N-terminal heptad repeat trimer of viral glycoprotein gp41. Here, a small-molecule HIV-1 inhibitor targeting chemokine coreceptor CCR5 on the host cell was integrated into the AP3 peptide, producing a novel dual-target inhibitor with improved activity against multiple HIV-1 strains including those resistant to the currently used anti-HIV-1 drug enfuvirtide. Its superior antiviral potency in comparison with the respective pharmacophoric moieties is in consonance with the dual binding of viral gp41 and host factor CCR5. Therefore, our work provides a potent artificial peptide-based bifunctional HIV-1 entry inhibitor and highlights the multitarget-directed ligands approach in the development of novel therapeutic anti-HIV-1 agents.

A comparative study on the metal complexes of an anticancer estradiol-hydroxamate conjugate and salicylhydroxamic acid

Hydroxamic acids bearing an (O,O) donor set are well-known metal-chelating compounds with diverse biological activities including anticancer activity. Since steroid conjugation with a pharmacophoric moiety may have the potential to improve this effect, a salicylhydroxamic acid–estradiol hybrid molecule (E2HA) was synthesized. Only minimal effect of the conjugation on the proton dissociation constants was observed in comparison to salicylhydroxamic acid (SHA).The complexation with essential metal ions (iron, copper) was characterized, since E2HA may exert its cytotoxicity through the binding of these ions in cells. UV–visible spectrophotometric and pH-potentiometric titrations revealed the formation of high-stability complexes, while the Fe(III) preference over Fe(II) was proved by cyclic voltammetry and spectroelectrochemical measurements.Complex formation with half-sandwich Rh(III)(η5-Cp*) and Ru(II)(η6-p-cymene) organometallic cations was also studied as it may improve the anticancer effect and the pharmacokinetic profile of the ligand. At equimolar concentration the speciation is complicated because of the presence of mononuclear and binuclear complexes. The complexes readily react with small molecules e.g. glutathione, 1-methylimidazole and nucleosides, having major effect on solution speciation, namely mixed-ligand complex formation and ligand displacement occur. These processes serve as models for the interactions with biomolecules in the body.E2HA exerted moderate anticancer activity (IC50 = 25–59 μM) in the tested three human cancer cell lines (Colo205, Colo320 and MCF-7), while being non-toxic on non-cancerous MRC-5 cells. Meanwhile, SHA was inactive in the same cells. Complexation with half-sandwich Rh(III) and Ru(II) cations had only a minor improvement on the cytotoxic effect of E2HA.

Novel Xanomeline-Containing Bitopic Ligands of Muscarinic Acetylcholine Receptors: Design, Synthesis and FRET Investigation

In the last few years, fluorescence resonance energy transfer (FRET) receptor sensors have contributed to the understanding of GPCR ligand binding and functional activation. FRET sensors based on muscarinic acetylcholine receptors (mAChRs) have been employed to study dual-steric ligands, allowing for the detection of different kinetics and distinguishing between partial, full, and super agonism. Herein, we report the synthesis of the two series of bitopic ligands, 12-Cn and 13-Cn, and their pharmacological investigation at the M1, M2, M4, and M5 FRET-based receptor sensors. The hybrids were prepared by merging the pharmacophoric moieties of the M1/M4-preferring orthosteric agonist Xanomeline 10 and the M1-selective positive allosteric modulator 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) 11. The two pharmacophores were connected through alkylene chains of different lengths (C3, C5, C7, and C9). Analyzing the FRET responses, the tertiary amine compounds 12-C5, 12-C7, and 12-C9 evidenced a selective activation of M1 mAChRs, while the methyl tetrahydropyridinium salts 13-C5, 13-C7, and 13-C9 showed a degree of selectivity for M1 and M4 mAChRs. Moreover, whereas hybrids 12-Cn showed an almost linear response at the M1 subtype, hybrids 13-Cn evidenced a bell-shaped activation response. This different activation pattern suggests that the positive charge anchoring the compound 13-Cn to the orthosteric site ensues a degree of receptor activation depending on the linker length, which induces a graded conformational interference with the binding pocket closure. These bitopic derivatives represent novel pharmacological tools for a better understanding of ligand-receptor interactions at a molecular level.

Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter

A new PET radiotracer 18F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of 18F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer-NET interaction, whereby a T-shaped π-π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.

Synthesis of bridged analogues of the antidepressant drug tianeptine. Representatives of a new ring system

In continuation of our efforts to synthesize new analogues of antidepressant drug tianeptine, we have incorporated a two-carbon bridge between the two nitrogen atoms of the 11-amino-dibenzo[c,f][1,2]thiazepine core structure of the tricyclic parent compound, resulting in a new tetracyclic ring system closely related to tianeptine. The synthetic route leading to the tetracyclic ring system is suitable for the introduction of various substituents to the amine-type nitrogen. The pharmacophore moiety characteristic of tianeptine has been introduced into the new tetracyclic molecule with two different methods. Altogether 32 new compounds are described in the present manuscript, 3 of them are also characterized by single-crystal X-ray diffraction.

Thiazolidinone-Heterocycle Frameworks: A Concise Review of Their Pharmacological Significance.

Molecular hybridization is deemed an optimistic approach in drug design and the discovery of novel biologically active molecules as it may advance their affinity and potency while concurrently decreasing associated resistance and side effects. Approximately 20 % of approved drugs were developed using this approach in the past few years. Thiazolidinone is one of the privileged pharmacophores in medicinal chemistry and is associated with various biological activities; it forms a functional unit in several FDA-approved drugs. Consequently, this pharmacophore has attracted the attention of many research groups to further explore its pharmacological relevance by coupling it with other pharmacophoric moieties. This review presents a concise account of scholarly research exploits directed at the biological activities of newly synthesized thiazolidinone-tagged molecular hybrids. Focused attention is given to the existing structural activity relationship in each compound library and the toxicity profile of potent compounds including in silico docking studies (where applicable). This work would provide a base on which new pharmaceuticals with improved potency can be modelled.

Investigation of Novel Quinoline-Thiazole Derivatives as Antimicrobial Agents: In Vitro and In Silico Approaches.

Infectious diseases are a major concern around the world. Today, it is an urgent need for new chemotherapeutics for infectious diseases. Because of that, our group designed, synthesized, and analyzed 14 new quinoline derivatives endowed with the pharmacophore moiety of fluoroquinolones primarily for their antimicrobial effects. Their cytotoxicity effects were tested against six bacterial and four fungal strains and NIH/3T3 cell line. Additionally, their action mechanisms were evaluated against DNA gyrase and lanosterol 14α-demethylase (LMD). Furthermore, to eliminate the potential side effects, the active compounds were evaluated against the aromatase enzyme. The experimental enzymatic results were evaluated for active compounds' binding modes using molecular docking and molecular dynamics simulation studies. The results were utilized to clarify the structure-activity relationship (SAR). Finally, compound 4m was the most potent compound for its antifungal activity with low cytotoxicity against healthy cells and fewer possible side effects, while compounds 4j and 4l can be used alone for special patients who are suffering from fungal infections in addition to the primer disease.

Synthesis of novel hybrid 1,5-disusbtituted 1H-tetrazol-5yl 4,5-dihydro [1,2,3]triazolo[1,5-a]pyrazin-6-ones via high-order MCR-S N 2/intramolecular [3 + 2] cycloaddition sequence

A facile and rapid synthesis of a family of new hybrid system 1,5-disusbtituted 1H-tetrazol-5yl 4,5-dihydro [1,2,3]triazolo[1,5-a]pyrazin-6-ones in moderate yields is described. Compounds were synthetized by a high-order multicomponent reaction (MCR) to give N-acylated 1,5-disubstituted tetrazoles followed, without chromatographic purification, by an S N 2/intramolecular [3 + 2] cycloaddition sequence. The target molecules could be useful in drug discovery processes because they contain two very important pharmacophoric moieties: 1,5-disubstituted tetrazole and 1,2,3- triazole.

Nematocidal alkaloids from the roots of Stemona mairei (H.Lév.)K.Krause and identification of their pharmacophoric moiety

Fifteen undescribed Stemona alkaloids, named as stemarines A–O (1–15), along with 25 known alkaloids (16–40), were isolated and identified from the roots of Stemona mairei (H.Lév.)K.Krause (Stemonaceae). Their structures were elucidated through the analysis of the NMR spectra, mass data, and computational chemistry. All the hitherto undescribed compounds possess a pyrrolo[1,2-α]azepine core structure but differ in important structural features, which reflects their nematocidal activities. Alkaloids 3–6 featured a carboxylic side chain and exhibited significant nematocidal activity against the nematode Caenorhabditis elegans. Transections of fresh roots combined with application of the Dragendorff’ reagent on the tissue indicated accumulation of alkaloids mainly in the epidermis and the pith. These results suggest the key pharmacophore of these alkaloids lies in the aliphatic side chain of these compounds and its spatial distribution in the roots indicate protective effects against underground herbivores.

A twenty-year journey exploring coumarin-based derivatives as bioactive molecules.

The coumarin core (i.e., 1-benzopyran-2 (2H)-one) is a structural motif highly recurrent in both natural products and bioactive molecules. Indeed, depending on the substituents and branching positions around the byciclic core, coumarin-containing compounds have shown diverse pharmacological activities, ranging from anticoagulant activities to anti-inflammatory, antimicrobial, anti-HIV and antitumor effects. In this survey, we have reported the main scientific results of the 20-years investigation on the coumarin core, exploited by the research group headed by Prof. Angelo Carotti (Bari, Italy) either as a scaffold or a pharmacophore moiety in designing novel biologically active small molecules.

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives.

The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine145 of SARS-CoV-2 MPRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 MPRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mechanism of inhibition. Furthermore, the analyses of the most recurrent pharmacophoric moieties and stereochemistry of chiral carbons were reported. The analyses of noncovalent and covalent in silico protocols, provided in this Perspective, would be useful for the scientific community to discover new and more efficient covalent SARS-CoV-2 MPRO inhibitors.

Development of new Alzheimer's disease drug candidates using donepezil as a key model.

Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by β-amyloid precipitation, β-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aβ aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.