Medicinal Chemistry最新文献

Pyridazinone analogs possess diverse types of pharmacological activities, such as anticancer, antimicrobial, anticonvulsant, analgesic, anti-inflammatory, antioxidant, antihypertensive, antisecretory, antiulcer, and other useful pharmacological activities. They also possess cyclooxygenase (COX) inhibitors, dipeptidyl peptidase inhibitors, phosphodiesterase inhibitors, glutamate transporter activators, adenosine receptor antagonists, serotonin receptors antagonists, lipooxygenase, cholinesterase, vasodilator, and anesthetics. Pyridazine rings are the essential structure for some marketed drugs, such as pimobendan, levosimendan as a cardiotonic drug, and emorfozan as an analgesic and anti-inflammatory (Non-steroidal anti-inflammatory drug) agent. So, researchers all over the world have paid attention to synthesizing various pyridazinone compounds mainly due to the ease of design and synthesis of different analogs and variables in the pharmacological responses. This review article focuses on the pharmacological activities of different pyridazine analogs.

The success of the TB control program is hampered by the major issue of drug-resistant tuberculosis (DR-TB). The situation has undoubtedly been made more difficult by the widespread and multidrug-resistant (XDR) strains of TB. The modification of existing anti-TB medications to produce derivatives that can function on resistant TB bacilli is one of the potential techniques to overcome drug resistance affordably and straightforwardly. In comparison to novel pharmaceuticals for drug research and progress, these may have a better half-life and greater bioavailability, be more efficient, and serve as inexpensive alternatives. Mycobacterium tuberculosis, which is drugsusceptible or drug-resistant, is effectively treated by several already prescribed medications and their derivatives. Due to this, the current review attempts to give a brief overview of the rifampicin derivatives that can overcome the parent drug's resistance and could, hence, act as useful substitutes. It has been found that one-third of the global population is affected by M. tuberculosis. The most common cause of infection-related death can range from latent TB to TB illness. Antibiotics in the rifamycin class, including rifampicin or rifampin (RIF), rifapentine (RPT), and others, have a special sterilizing effect on M. tuberculosis. We examine research focused on evaluating the safety, effectiveness, pharmacokinetics, pharmacodynamics, risk of medication interactions, and other characteristics of RIF analogs. Drug interactions are especially difficult with RIF because it must be taken every day for four months to treat latent TB infection. RIF continues to be the gold standard of treatment for drug-sensitive TB illness. RIF's safety profile is well known, and the two medicines' adverse reactions have varying degrees of frequency. The authorized once-weekly RPT regimen is insufficient, but greater dosages of either medication may reduce the amount of time needed to treat TB effectively.

Background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers severe drawbacks.

Objective: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866. To this aim, the new anticancer agents were based on benzene, pyridazine, or benzothiazole moieties as a cap group instead of the pyridine unit found in FK866 and other NAMPT inhibitors.

Methods: The new compounds, prepared exploiting standard heterocycle chemistry and coupling reactions (e.g., formation of amides, ureas, and cyanoguanidines, copper-mediated azide-alkyne cycloaddition), have been fully characterized using NMR and HRMS analyses. Their activity has been evaluated using cytotoxicity and intracellular NAD depletion assays in the human pancreatic cancer cell line MiaPaCa-2.

Results: Among the 14 products obtained, compound 28, bearing a pyridazine unit as the cap group and a thiophene moiety as the tail group, showed 6.7 nanomolar inhibition activity in the intracellular NAD depletion assay and 43 nanomolar inhibition in the MiaPaCa-2 cells cytotoxicity assay, comparable to that observed for FK866.

Conclusion: The positive results observed for some newly synthesized molecules, particularly those carrying a thiophene unit as a tail group, indicate that they could act as in vivo anti-pancreatic cancer agents.

Background: Recent research has shown that ferulic acid (FA, trans-4-hydroxy-3- methoxycinnamic acid) has remarkable antioxidant properties and a wide range of biological activities. Conjugation of two or more biologically active compounds to produce a novel molecular scaffold is justified by the need to enhance biological activity against a single target or obtain a conjugate that behaves as a multi-target-directed ligand. In addition, the conjugation strategy decreases dose-dependent side effects by promoting the use of smaller doses of conjugated components to treat the disease. Moreover, the patient's compliance is positively affected when conjugating two active compounds into a single more active compound as this reduces the number of pills to be taken daily.

Objective: This study aims to shed light on studies that design and synthesize FA-based hybrid compounds with enhanced biological activities and to in silico assess these compounds as potential drug candidates.

Methods: The conjugate compounds were found by searching the literature using the keywords (ferulic acid-based hybrid or ferulic acid-based conjugate). To study conjugate pharmacokinetic parameters and toxicity (ADMET), software suites from Biovia Inc. (San Diego, California) were integrated into Discovery Studio 4.5. The structures were created using ChemDraw Ultra 7.0.

Results: 14 conjugates exhibiting variable biological activities were collected and three of them (compounds 3,5, and 6) in addition to the cis FA (compound 12) are the best-predicted compounds with low Daphnia toxicity and hepatotoxicity with acceptable pharmacokinetic properties.

Conclusion: Cis FA, FA conjugates 3,5, and 6 act as good drug candidates that can be used to modify new hits.

Background: Drug-resistant infections kill hundreds of thousands of people globally every year. In previous work, we found that tri-methoxy- and pyridine-substituted imidazoles show strong antibacterial activities.

Objective: The aim of this work was to investigate the antibacterial activities and bacterial resistances of imidazoles bearing an aromatic heterocyclic, alkoxy, or polycyclic moiety on the central ring.

Methods: Three series of 2-cyclopropyl-5-(5-(6-methylpyridin-2-yl)-2-substituted-1H-imidazol-4- yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazoles (13a-e, 14a-d, and 15a-f) were synthesized and their antibacterial activity was evaluated. The structures were confirmed by their ¹H NMR, ¹³C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive, Gramnegative, and multidrug-resistant bacterial strains.

Results: More than half of the compounds showed moderate or strong antibacterial activity. Among them, compound 13e (MICs = 1-4 μg/mL) showed the strongest activity against Gram-positive and drug-resistant bacteria as well as high selectivity against Gram-negative bacteria. Furthermore, it showed no cytotoxicity against HepG2 cells, even at 100 μM, and no hemolysis at 20 μM.

Conclusion: These results indicate that compound 13e is excellent candicate for further study as a potential antibacterial agent.

Benzimidazole nucleus is a predominant heterocycle displaying a wide spectrum of pharmacological activities. The privileged nature of the benzimidazole scaffold has been revealed by its presence in most small molecule drugs and in its ability to bind multiple receptors with high affinity. A literature review of the scaffold reveals several instances where structural modifications of the benzimidazole core have resulted in high-affinity lead compounds against a variety of biological targets. Hence, this structural moiety offers opportunities to discover novel, better, safe and highly potent biological agents. The goal of the present review is to compile the medicinal properties of benzimidazole derivatives with a focus on SAR (Structure-Activity Relationships).

Introduction: Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5, COX-2, pro-inflammatory enzymes, and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases.

Objective: Herein, we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters.

Methods: The synthesis was based on an In silico study of a library of cinnamic amide hybrids with glycine, γ- aminobutyric, and L - glutamic acids. Drug-likeness and ADMET properties were subjected to In silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of N,N,-diisopropyl-Nethylamine.

Results: The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds, such as lipoxygenase, cyclooxygenase-2, lipid peroxidation inhibitors, and antiinflammatories, were tested in vitro. The compounds exhibited LOX inhibition with IC₅₀ values in the low μM region).

Conclusion: Compounds 18a, 23b, and 11c are strong lipid peroxidation inhibitors (99%, 78%, and 92%). Compound 28c inhibits SLOX-1 with IC₅₀ =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC₅₀ 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The In silico ADMET properties of 14c and 11a support their drug-likeness.

Introduction: Inflammation can be defined as a complex biological response that is produced by body tissues to harmful agents like pathogens, irritants, and damaged cells and thereby acts as a protective response incorporating immune cells, blood vessels, and molecular mediators. Histamine, serotonin, bradykinin, leukotrienes (LTB4), prostaglandins (PGE2), prostacyclins, reactive oxygen species, proinflammatory cytokines like IL-1, IL-11, TNF- anti-inflammatory cytokines like IL-4, IL-10, IL-11, IL-6 and IL-13, etc. all have different effects on both pro and anti-inflammatory mediators. Incorporation of combinatorial chemistry and computational studies have helped the researchers to design xanthones moieties with high selectivity that can serve as a lead compound and help develop potential compounds that can act as effective COX-2 inhibitors. The study aims to design and develop different series of substituted hydroxyxanthone derivatives with anti-inflammatory potential.

Methods: The partially purified synthetic xanthone derivatives were orally administered to the carrageenan induced paw oedemic rat models at the dose of 100 mg/kg, and their effect in controlling the degree of inflammation was measured at the time interval of 30 min, 1, 2, 3, 4 and 6 hrs. respectively. Further, these compounds were also subjected to modern analytical studies like UV, IR, NMR and mass spectrometry or their characterization.

Results: The results drawn out of the in silico, in vitro, in vivo and analytical studies concluded that the hydroxyxanthone derivatives can obstruct the enzyme COX-2 and produce anti-inflammatory action potentially.

Conclusion: With the aim to evaluate the compounds for their anti-inflammatory activity, it was observed that the newly designed xanthonic compounds also possess a safe toxicity margin and hence can be utilized by the researchers to develop hybrid xanthonic moieties that can specifically target the enzyme COX-2.

Chromenes are a significant family of heterocyclic chemicals that have a wide range of biological applications, a simple chemical structure, and only mildly undesirable side effects. The synthesis of a wide range of chromene analogs that displayed unexpected behaviors via numerous mechanisms was investigated by a number of different research teams, which led to the discovery of multiple pathways for their synthesis. In addition, different chromene-fused heterocycles exhibit a wide variety of fascinating biological actions, including those that are anticancer, anticonvulsant, antibacterial, anticholinesterase, antituberculosis, and anti-diabetic. In light of this, the purpose of this study is to highlight the many synthesis techniques and antibacterial activity associated with chromene-fused heterocyclic compounds. Moreover, such research can open avenues for exploring other therapeutic applications of these compounds in various disease areas, as their biological activities extend beyond antibacterial effects.

Background: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERβ). The positive effects of ERβ ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERβ an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERβ ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment.

Objective: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated.

Methods: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively.

Results: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 μM. Interestingly, treatment with 10 μM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2.

Conclusion: Altogether, these results show the two new potential β-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.