Piperazine Scaffold Research Articles

Development of selective sigma-1 receptor ligands with antiallodynic activity: A focus on piperidine and piperazine scaffolds

The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compounds 12a (AD353) and 12c (AD408) exhibited negligible in vitro cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, 12a exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds.

Recently Adopted Synthetic Protocols for Piperazines: A Review

Piperazines, a class of heterocyclic compounds, have garnered significant attention in the field of organic synthesis due to their diverse pharmacological activities and widespread applications in medicinal chemistry. This review provides a comprehensive overview of the recent advancements in the synthesis of piperazines, highlighting innovative methodologies, novel reagents, and green synthesis approaches adopted by researchers. The synthesis of piperazines has witnessed remarkable progress, with a focus on developing efficient and sustainable synthetic routes. Various strategies, such as transition-metal-catalyzed reactions, microwave-assisted synthesis, photo-redox reactions, and bio-inspired methods, have emerged as powerful tools for constructing piperazine scaffolds. The review also encompasses discussions on the stereochemistry and regioselectivity issues associated with piperazine synthesis, shedding light on the intricacies of achieving specific substitution patterns. The impact of newly synthesized piperazines in drug discovery and development is also explored, emphasizing the therapeutic potential of these compounds in various disease areas. In conclusion, this review provides a comprehensive and up-to-date account of the recent advancements in piperazine synthesis, offering insights into the current state of the field and guiding future research directions. The integration of innovative methodologies and the exploration of sustainable practices underscore the ongoing efforts to streamline the synthesis of piperazines, contributing to the expansion of their applications in medicinal chemistry and related disciplines.

Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold.

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.

Dual 5-HT6/SERT ligands for mitigating neuropsychiatric symptoms of dementia exerting neuroprotection against amyloid-β toxicity, memory preservation, and antidepressant-like properties

In light of the biological targets alterations in dementia patients suffering from neuropsychiatric symptoms, particularly in the 5-HT6 receptor and SERT transporters, this study aimed to develop dual-acting molecules targeting both these targets. By combining a 5-substituted indole with piperazine scaffolds, we synthesized molecules with nanomolar affinities for these sites, avoiding interaction with off-targets detrimental to dementia patients. Preliminary pharmacodynamic and ADMET assays let the identification of compound 15 as a lead molecule. In vitro studies showed that 15 provided neuroprotection against Aβ toxicity and reduced the levels of proapoptotic enzymes: caspase 3 and 7. In vivo, 15 reversed MK-801-induced memory deficits and exhibited antidepressant-like effects. Further studies showed that acute administration of compound 15 at a dose of 5 mg/kg increased BDNF levels, which are crucial for supporting neuronal survival and potentially slowing cognitive decline in dementia. These findings suggest 15's potential as a therapeutic for behavioral and psychological symptoms of dementia (BPSD), warranting further investigation.

Miniaturized click chemistry and direct screening facilitate the discovery of triazole piperazine SARS-CoV-2 Mpro inhibitors with improved metabolic stability.

The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design and develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on the efficient discovery of potent non-covalent non-peptide-derived Mpro inhibitors using miniaturized click chemistry and direct screening. Based on the privileged piperazine scaffold, 68 triazole-containing derivatives were assembled and screened. Notably, representative compound C1N46 (IC50 = 1.87 μM, EC50 = 6.99 μM, CC50 > 100 μM) displayed potent inhibition activity against Mpro and showed promising anti-SARS-CoV-2 properties in vitro. Additionally, C1N46 exhibited improved liver microsome stability compared to lead compound GC-14. Docking studies predicted a multi-site binding mode of the triazole-based compounds. In conclusion, our studies validate the efficacy and feasibility of click chemistry in rapidly discovering antiviral agents.

Novel multi-target ligands of dopamine and serotonin receptors for the treatment of schizophrenia based on indazole and piperazine scaffolds–synthesis, biological activity, and structural evaluation

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1–16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

Trifluoromethylpyridine piperazine derivatives: synthesis and anti-plant virus activity.

The cucumber mosaic virus (CMV) is well-known for its expansive host range and distribution, resulting in a detrimental effect on agricultural production, thus making it imperative to implement measures for its control. Novel compounds S1-S28 were synthesized by connecting trifluoromethyl pyridine, amide and piperazine scaffolds. Bioassays indicated that most of the synthesized compounds exhibited good curative effects against CMV, with half maximal effective concentration (EC50 ) values of compounds S1, S2, S7, S8, S10, S11, S15, and S28 being 119.6, 168.9, 197.6, 169.1, 97.9, 73.9, 224.4, and 125.2μg mL-1 , respectively, which were lower than the EC50 of ningnanmycin (314.7μg mL-1 ). Compounds S5 and S8 exhibited protective activities with EC50 of 170.8 and 95.0μg mL-1 , respectively, which were lower than ningnanmycin at 171.4μg mL-1 . The inactivation activities of S6 and S8 at 500 μg mL-1 were remarkably high at 66.1% and 78.3%, respectively, surpassing that of ningnanmycin (63.5%). Additionally, their EC50 values were more favorable at 22.2 and 18.1μg mL-1 , respectively, than ningnanmycin (38.4μg mL-1 ). And molecular docking and molecular dynamics simulation showed compound S8 had better binding with CMV-coat protein, providing a possible explanation for the anti-CMV activity of compound S8. Compound S8 showed a strong binding affinity to CMV-coat protein and impacted the self-assemble of CMV particles. Compound S8 could be a potential lead compound for discovering a new anti-plant virus candidate. © 2023 Society of Chemical Industry.

Discovery and Crystallographic Studies of Nonpeptidic Piperazine Derivatives as Covalent SARS-CoV-2 Main Protease Inhibitors.

The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived Mpro inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, GD-9 was identified as the most potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 μM) and good antiviral potency against SARS-CoV-2 (EC50 = 2.64 μM), similar to that of remdesivir (EC50 = 2.27 μM). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.

Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity.

The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (Mpro) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide Mpro inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound GC-14 inhibits Mpro with high potency (IC50 = 0.40 μM) and displays excellent antiviral activity (EC50 = 1.1 μM), being more potent than Remdesivir. Notably, GC-14 exhibits low cytotoxicity (CC50 > 100 μM) and excellent target selectivity for SARS-CoV-2 Mpro (IC50 > 50 μM for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19.

The piperazine scaffold for novel drug discovery efforts: the evidence to date

ABSTRACT Introduction . Piperazine is a structural element present in drugs belonging to various chemical classes and used for numerous different therapeutic applications; it has been considered a privileged scaffold for drug design. Areas covered The authors have searched examples of piperazine-containing compounds among drugs recently approved by the FDA, and in some research fields (nicotinic receptor modulators, compounds acting against cancer and bacterial multi-drug resistance), looking in particular to the design behind the insertion of this moiety. Expert opinion Piperazine is widely used due to its peculiar characteristics, such as solubility, basicity, chemical reactivity, and conformational properties. This moiety has represented an important tool to modulate pharmacokinetic and pharmacodynamic properties of drugs.

Piperazine scaffold in drugs – structural and pharmaceutical points of view

Piperazine scaffold in drugs – structural and pharmaceutical points of view

Structure–activity relationship of three new piperazine derivates with anxiolytic-like and antidepressant-like effects

Anxiety and depression are common mental disorders affecting millions of people worldwide. Unsatisfactory clinical outcomes with the use of the available pharmacological interventions among some patients demand newer drugs with proven efficacy, safety, and tolerability profile. In this study, the LQFM211, LQFM213, and LQFM214 were designed from the piperazine scaffold and administered orally in mice. These mice were later evaluated in the open field, elevated plus maze, and forced swimming tests to assess the exploratory, anxiolytic, and antidepressant-like activities, respectively. The mechanism of action of these new derivatives was evaluated using flumazenil (benzodiazepine antagonist) and WAY100635 (5-HT1A receptor antagonist). Unlike LQFM214, the LQFM211 and LQFM213 elicited anxiolytic and antidepressant-like effects. The blockade of the effect of LQFM213 by WAY100635 suggests the involvement of the serotonergic pathway.

Design and construction of a stereochemically diverse piperazine-based DNA-encoded chemical library

Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine scaffold. Using a wide range of building blocks, a diverse library of 77 million compounds was produced. Cheminformatic analysis demonstrates that this library occupies a wide swath of chemical space, and that the piperazine scaffolds confers different shape diversity compared to the commonly used triazine core.

In silico validation of novel inhibitors of malarial aspartyl protease, plasmepsin V and antimalarial efficacy prediction

Plasmepsin V (Plm V) is an essential aspartic protease required for survival of the malaria parasite, Plasmodium falciparum (Pf). Plm V is required for cleaving the PEXEL motifs of many Pf proteins and its inhibition leads to a knockout effect, indicating its suitability as potential drug target. To decipher new inhibitors of PfPlm V, molecular docking of four HIV-1 protease inhibitors active against PfPlmV was performed on Glide module of Schrödinger suite that supported saquinavir as a lead drug, and therefore, selected as a control. Saquinavir contains an important hydroxyethylamine (HEA) pharmacophore, which was utilized as backbone coupled with piperazine scaffold to build new library of compounds. Newly designed HEA compounds were screened virtually against Plm V. Molecular docking led to a few hits (1 and 3) with higher docking score over the control drug. Notably, compound 1 showed the highest docking score (–11.90 kcal/mol) and XP Gscore (–11.948 kcal/mol). The Prime MMGBSA binding free energy for compound 1 (–60.88 kcal/mol) and 3 (–50.96 kcal/mol) was higher than saquinavir (–37.51 kcal/mol). The binding free energy for the last frame of molecular dynamic simulation supported compound 1 (–92.88 kcal/mol) as potent inhibitor of PfPlm V over saquinavir (–72.77 kcal/mol), and thus, deserves experimental validations in culture and subsequently in animal models. Communicated by Ramaswamy H. Sarma

Recent advances in the synthesis of piperazine based ligands and metal complexes and their applications.

The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of antidepressants (amoxapine), antipsychotics (bifeprunox), antihistamines (cyclizine and oxatomide), antifungals (itraconazole), antibiotics (ciprofloxacin), etc. This is one of the reasons why piperazine based compounds are gaining prominence in today's research. In addition to the ring carbons, substitution in the nitrogen atom of piperazine not only creates potential drug molecules but also makes it unique with versatile binding possibilities with metal ions. Piperazine ring-based compounds find their application in biological systems with antihistamine, anticancer, antimicrobial and antioxidant properties. They have also been successfully used in the field of catalysis and metal organic frameworks (MOFs). The present review focuses on the synthesis and application of different piperazine derivatives and their metal complexes having diverse applications.

Hancockiamides: phenylpropanoid piperazines from Aspergillus hancockii are biosynthesised by a versatile dual single-module NRPS pathway.

The hancockiamides are an unusual new family of N-cinnamoylated piperazines from the Australian soil fungus Aspergillus hancockii. Genomic analyses of A. hancockii identified a biosynthetic gene cluster (hkm) of 12 genes, including two single-module nonribosomal peptide synthetase (NRPS) genes. Heterologous expression of the hkm cluster in A. nidulans confirmed its role in the biosynthesis of the hancockiamides. We further demonstrated that a novel cytochrome P450, Hkm5, catalyses the methylenedioxy bridge formation, and that the PAL gene hkm12 is dispensable, but contributes to increased production of the cinnamoylated hancockiamides. In vitro enzymatic assays and substrate feeding studies demonstrated that NRPS Hkm11 activates and transfers trans-cinnamate to the piperazine scaffold and has flexibility to accept bioisosteric thienyl and furyl analogues. This is the first reported cinnamate-activating fungal NRPS. Expression of a truncated cluster lacking the acetyltransferase gene led to seven additional congeners, including an unexpected family of 2,5-dibenzylpiperazines. These pleiotropic effects highlight the plasticity of the pathway and the power of this approach for accessing novel natural product scaffolds.

Further SAR on the (Phenylsulfonyl)piperazine Scaffold as Inhibitors of the Aedes aegypti Kir1 (AeKir) Channel and Larvicides.

Zika virus (ZIKV), dengue fever (DENV) and chikungunya (CHIKV) are arboviruses that are spread to humans from the bite of an infected adult female Aedes aegypti mosquito. As there are no effective vaccines or therapeutics for these diseases, the primary strategy for controlling the spread of these viruses is to prevent the mosquito from biting humans through the use of insecticides. Unfortunately, the commonly used classes of insecticides have seen a significant increase in resistance, thus complicating control efforts. Inhibiting the renal inward rectifier potassium (Kir) channel of the mosquito vector Aedes aegypti has been shown to be a promising target for the development of novel mosquitocides. We have shown that Kir1 channels play key roles in mosquito diuresis, hemolymph potassium homeostasis, flight, and reproduction. Previous work from our laboratories identified a novel (phenylsulfonyl)piperazine scaffold as potent AeKir channel inhibitors with activity against both adult and larval mosquitoes. Herein, we report further SAR work around this scaffold and have identified additional compounds with improved in vitro potency and mosquito larvae toxicity.

An Overview of Piperazine Scaffold as Promising Nucleus for Different Therapeutic Targets.

Piperazine scaffolds are a group of heterocyclic atoms having pharmacological values and showing significant results in pharmaceutical chemistry. Piperazine has a flexible core structure for the design and synthesis of new bioactive compounds. These flexible heterogenous compounds exhibit various biological roles, primarily anticancer, antioxidant, cognition enhancers, antimicrobial, antibacterial, antiviral, antifungal, antiinflammatory, anti-HIV-1 inhibitors, antidiabetic, antimalarial, antidepressant, antianxiety and anticonvulsant activities, etc. In the past few years, researchers focused on the therapeutic profile of piperazine synthons for different biological targets. The present review highlights the development in designing pharmacological activities of nitrogen-containing piperazine moiety as a therapeutic agent. The extensive popularity of piperazine as a drug of abuse and their vast heterogeneity research efforts over the last years motivated the new investigators to further explore this area.

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges.

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C2‐ or C3‐bridges across the 2‐ and 6‐position. At first, a three‐step, one‐pot procedure was developed to obtain reproducibly piperazine‐2,6‐diones with various substituents at the N‐atoms in high yields. Three strategies for bridging of piperazine‐2,6‐diones were pursued: 1. The bicyclic mixed ketals 8‐benzyl‐6‐ethoxy‐3‐(4‐methoxybenzyl)‐6‐(trimethylsilyloxy)‐3,8‐diazabicyclo[3.2.1]octane‐2,4‐diones were prepared by Dieckmann analogous cyclization of 2‐(3,5‐dioxopiperazin‐2‐yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine‐2,6‐diones led to 3‐(3,5‐dioxopiperazin‐2‐yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9‐benzyl‐6‐hydroxy‐3‐(4‐methoxybenzyl)‐3,9‐diazabicyclo[3.3.1]nonane‐2,4‐dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N‐(2,4‐dioxo‐3,9‐diazabicyclo[3.3.1]nonan‐6‐yl)‐2‐methylpropane‐2‐sulfinamides in >66 % yield. 3. Transformation of a piperazine‐2,6‐dione with 1,4‐dibromobut‐2‐ene and 3‐halo‐2‐halomethylprop‐1‐enes provided 3,8‐diazabicyclo[3.2.1]octane‐2,4‐dione and 3,9‐diazabicyclo[3.3.1]nonane‐2,4‐dione with a vinyl group at the C2‐ or a methylene group at the C3‐bridge, respectively. Since bridging via sulfinylimines and the one‐pot bridging with 3‐bromo‐2‐bromomethylprop‐1‐ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge

Identifying new piperazine-based PARP1 inhibitors using text mining and integrated molecular modeling approaches

One of the important molecular targets for antitumor drug discovery is the polyadenosine diphosphate-ribose polymerase-1 (PARP1) enzyme. It is linked with various biological functions including DNA repair and apoptosis. It is primarily a nuclear enzyme linked to chromatin, which is activated by DNA damage. Improved expression of PARP1 in melanomas, breast cancer, lung cancer and other neoplastic diseases is often observed. A tremendous PARP research concerning cancer and ischemia is progressing very rapidly. There are currently four PARP1 inhibitors approved by the FDA on the market, namely Olaparib, Rucaparib, Niraparib and Talazoparib. All of these molecules are non-selective inhibitors of PARP1. Currently there is an urgent need for novel and selective PARP1 inhibitors. In this work, asmall molecule database (Specs SC) were used to identify the new selective lead inhibitors of PARP1. Piperazine scaffold is an important fragment that is used in many currently used FDA approved drugs in different diseases including PARP1 inhibitor Olaparib. Thus, based on text mining studies, 4674 compounds thatinclude piperazine fragments were identified and virtually screened at the binding pocket of target protein PARP1. Compounds that have high docking scores were used in molecular dynamics (MD) simulations. Free energy calculations were also performed to compare the predicted binding energies with known PARP1 inhibitors. The critical amino acid interactions of these newly identified hits in the binding pocket were also investigated in detail for better understanding of the structural features required for next generation PARP1 inhibitors. Thus, here together with combination of text-mining and integrated molecular modeling approaches, we identified novel piperazine-based hits against PARP1 enzyme.Communicated by Ramaswamy H. Sarma