Medicinal Chemistry最新文献

Considering the necessity for broad synthetic operations, integrating various reactions into a single pot operation is an intriguing approach to improve synthetic efficiency. One-pot operations may serve as an effective way to minimize the amount of chemical waste generated, save time, avoid multiple purification processes, accomplish numerous transformations, and make multiple bonds in one pot. Therefore, "pot economy" should be considered while designing a synthesis process, since a one-pot reaction can be effective and environmentally safe. Outstanding synthesis has rapidly increased over the last ten years. This study's main goal was to illustrate various one-pot methods that lead to advantageous synthesis.

Introduction: Epilepsy encompasses numerous syndromes characterized by spontaneous, intermittent, and abnormal electrical activity in the brain. Affecting about 1-2% of the population, it is estimated that approximately 30-40% of patients experience refractory epilepsy, which does not respond to traditional anticonvulsant drugs.

Methods: Therefore, developing novel, safe, and effective antiepileptic drugs remains a medical need. In this study, we synthesized a series of isoindoline-1,3-dione derivatives and evaluated their anticonvulsant effects.

Results: Compounds (2a-j) and (5) were obtained with yields ranging from 52-97%. These compounds were assessed for their protective effects on the following parameters: a) time to first seizure (seizure latency), b) seizure duration, and c) mortality rate post-seizure. The most active compound, (2a), increased seizure latency, reduced seizure duration, and lowered the mortality rate.

Conclusion: These findings indicate that compound (2a) is a promising new anticonvulsant prototype, offering an alternative to current anticonvulsant drugs.

Objectives: Malaria continues to be the primary cause of mortality worldwide, and timely recognition and prompt intervention are crucial in mitigating adverse consequences. This review article aims to examine the effectiveness and structural characteristics of quinoline-based compounds as antimalarial agents. It specifically focuses on their therapeutic effects as well as potential prospects for exploring structure-activity relationship (SAR). In addition, this study aims to identify lead compounds that can efficiently battle multidrug-resistant forms of Plasmodium falciparum and Plasmodium vivax.

Methods: A comprehensive review was conducted to evaluate the effectiveness of quinoline-based antimalarial medications in eradicating P. falciparum and P. vivax. The mechanism of action and SAR of these compounds were analyzed.

Results: Quinoline-based antimalarials demonstrated significant effectiveness in eliminating P. falciparum parasites, particularly in regions severely impacted by malaria, including Africa and Asia. These compounds were found to exhibit tolerance and immune-modulating properties, indicating their potential for more widespread utilization. The investigation identified various new quinoline compounds with improved antimalarial activity, including metal-chloroquine complexes, diaminealkyne chloroquines, and cinnamoylated chloroquine hybrids. This study explored different mechanisms by which these compounds interact with parasites, including their ability to accumulate in the parasite's acidic food vacuoles and disrupt heme detoxification. The derivatives demonstrated strong efficacy against chloroquine-resistant strains and yielded positive results.

Conclusion: Quinoline-based compounds represent a promising avenue for combating malaria due to their demonstrated efficacy against P. falciparum and P. vivax parasites. Further research on their mechanisms of action and SAR could lead to the development of more effective antimalarial medications.

Background: Chagas disease has an ineffective drug treatment despite efforts made over the last four decades. The carbonic anhydrase of Trypanosoma cruzi (α-TcCA) has emerged as an interesting target for the design of new antiparasitic compounds due to its crucial role in parasite processes.

Objective: The aim in this study was identify potential α-TcCA inhibitors with trypanocidal activity.

Methods: A maximum common substructure (MCS) and molecular docking were used to carried out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an in vitro model against the NINOA strain of Trypanosoma cruzi, and cytotoxicity was determined in a murine model of macrophage cells J774.2.

Results: Five sulfonamide derivatives (C7, C9, C14, C19, and C21) had the highest docking scores (-6.94 to -8.31 kcal/mol). They showed key residue interactions on the active site of the α-TcCA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC₅₀) values of 26, 61.6, and 49 μM, respectively, against NINOA strain epimastigotes of Trypanosoma cruzi.

Conclusion: Compounds C7, C9, and C21 showed trypanocidal activity; therefore, these results encourage the development of new trypanocidal agents based in their scaffold.

Background: Over the past ten years, a remarkable number of changes have occurred in the field of cancer drug research. Most anticancer drugs from the first generation work by breaking down DNA, preventing its production, interfering with cell division processes, or attaching to microtubules. The potential use of tryptanthrin as well as its analogues is well documented for anticancer properties.

Objective: To design a novel hybrid of tryptanthrin analogs with expected anticancer activity.

Methods: By changing the C-6 carbonyl position of the tryptanthrin molecule, a set of 72 derivatives of substituted-6-benzylidine-6H-indolo[2,1-b] quinazoline-12-one was developed. These ligands were screened in silico using Schrodinger Glide extra precision docking against DNA topoisomerase using doxorubicin and teniposide as references to identify their potential anticancer properties. Further, these ligands were subjected to an in silico ADMET study to identify their drug likeliness.

Results: Combined results of molecular docking and in silico ADMET study suggest that out of the total 72 ligands, 6 ligands RC 51, RC 29, RC 42, RC 3, RC 54, and RC 63 were showing very better binding affinity than the natural ligand adenylyl-imidodiphosphate and the two standard reference drugs- doxorubicin and teniposide.

Conclusion: Our computational approach was successful in identifying ligands that are potentially potent topoisomerase inhibitors. These can be tested further using in vitro and in vivo analysis.

HDAC8 is associated with several disease conditions as well as various cancers of several organs and hematological malignancies. To counter such pathophysiological and disease conditions, inhibition of HDAC8 may be a promising approach for anticancer drug development. In this article, a detail of arylcarboxamide-based potential HDAC8 inhibitors has been outlined. Considering their binding pattern of interactions along with the chemical features, effective and selective novel HDAC8 inhibitors can be designed further. Therefore, modification of these compounds provides greater possibilities for the development of novel HDAC8 inhibitors. Nevertheless, structural modification of such arylcarboxamide derivatives may be able to produce potent dual-inhibitory compounds along with HDAC8 inhibition. Thus, this article is quite useful for exploring and identifying several possibilities for arylcarboxamide-based HDAC8 inhibitors. Moreover, it can be concluded that further study of the arylcarboxamide-based HDAC8 inhibitors can be effectively used for the treatment of different cancerous and non-cancerous diseases.

Indazole, a heterocyclic molecule, has emerged as a useful scaffold in synthetic and medicinal chemistry due to its broad biological activity and ease of synthesis. This article thoroughly analyzes unique synthetic methods used to diversify indazole derivatives, such as metal-catalyzed reactions, ecologically friendly approaches, and novel multicomponent reactions. These advances have increased the efficiency and selectivity of indazole synthesis and its structural variety, paving the path for new biological applications. Furthermore, indazole-based compounds have demonstrated promising biological activities, particularly as anticancer, antibacterial, and anti-inflammatory medicines. This review summarizes the present state of indazole research, focusing on synthetic techniques and biological features that make indazole an attractive target for future drug discovery.

Introduction: A series of novel 2-((3,5-diphenylpyrazin-2-yl)amino)-1-(piperidin-1- yl/pyrrolidin-1-yl)ethanone derivatives (5a-5l) were synthesized and evaluated for their tuberculosis activity using the standard strain H37Rv and two other clinically isolated multidrug-resistant strains with different resistances.

Methods: All compounds 5a-5l showed promising results in tuberculosis activity. Among them, 5g and 5i demonstrated remarkable activity at 5 μg/mL against H37Rv and three other MDR strains. The compounds 5c, 5d, and 5f were sensitive, showing inhibition between 15-25 μg/mL against M. tuberculosis growth. In-silico docking studies were conducted for 5a-5l using the 2FUM protein of M. tuberculosis.

Results: These studies revealed that compounds 5g and 5i exhibited strong interactions with the MTB protein, with binding energies of -9.85 kcal/mol and -10.74 kcal/mol, respectively, and inhibitory concentrations of 0.38 μM and 0.77 μM.

Conclusion: Moreover, these motifs also displayed good binding energy coupled with favorable minimum inhibitory concentrations (MIC).