Saghi Sepehri

This review highlights pyridinium salts as key intermediates in synthesis, medicinal chemistry, sustainable processes, and emerging applications.

Leishmaniasis is a severely neglected intracellular protozoan disease caused by infection with parasites of the Leishmania genus, affecting over 98 countries globally. Presently, the infection threatens the health of more than 350 million people globally, resulting in an estimated 60,000 deaths yearly from both visceral and cutaneous forms of the parasite. In present research, a novel series of thiazolidine-4-one analogues (7a-g) was synthesized and evaluated against Leishmania major. In vitro assays demonstrated using Leishmania major promastigotes and amastigotes, while cytotoxicity was assessed on the J_774.A1 macrophage cell line. All tested compounds exhibited inhibitory effects against promastigotes, with compounds 7a (IC₅₀ = 34.97 μM), 7c (IC₅₀ = 40.79 μM), and 7b (IC₅₀ = 62.59 μM) showing the highest potency. Against the amastigote form, analogues 7a, 7b, and 7d demonstrated notable efficacy, with IC₅₀ values of 354.53 μM, 665.72 μM, and 746.59 μM, respectively. Flow cytometry analysis revealed that these compounds induce multiple stages of apoptosis, including both early and late apoptosis, as well as necrosis, in promastigotes. Furthermore, some derivatives exhibited moderate cytotoxic effects on macrophages. Compounds 7a and 7b demonstrated the highest selectivity indices (SI) of 6.23 and 3.22, respectively. Overall, the tested compounds showed stronger anti-promastigote activity compared to their anti-amastigote effects. In silico analyses indicated that the thiazolidine-4-one derivatives possess satisfactory drug-likeness characteristics and identified probable metabolic sites via major cytochrome P450 enzymes. Finally, molecular docking and molecular dynamics simulations were performed at the active site of Leishmania major pteridine reductase 1 (LmPTR1). They revealed that the most active compounds, 7a and 7c, adopt favorable binding orientations and maintain stable interactions with key residues of LmPTR1, correlating with their enhanced in vitro activity. Additionally, RMSD, RMSF, hydrogen bonds, Rg, SASA, PCA, and energy analysis during molecular dynamics simulations indicated stable binding of two compounds with LmPTR1. Furthermore, the results from docking and molecular dynamics simulations demonstrated that hydrophobic interactions were critical in the binding of these compounds to LmPTR1.

This study presents an integrated computational framework that combines three‐dimensional quantitative structure–activity relationship (3D‐QSAR) modeling with molecular dynamics (MD) simulations to advance the rational design of triazole‐based urease inhibitors. Given the role of urease as a central virulence factor in Helicobacter pylori and its increasing relevance in antibiotic‐resistant infections, effective predictive methodologies are essential for early‐stage inhibitor development. A dataset of 54 triazole derivatives was examined using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), generating statistically robust and predictive models that elucidate the steric, hydrophobic, and hydrogen‐bonding features underlying inhibitory potency. These insights, supported by molecular docking and structure–activity relationship analyses, informed the construction of a pharmacophore model used to screen the ZINC database. Several candidate molecules, including ZINC84668437, ZINC84669798, and ZINC244633273, emerged as computationally promising and demonstrated favorable predicted druglikeness and ADMET characteristics. MD simulations were subsequently employed to evaluate the dynamic stability and conformational behavior of the ligand–urease complexes, reinforcing the coherence of the integrated computational workflow. The primary contribution of this work resides in its methodological integration of complementary in silico approaches rather than in experimental validation. Although the findings offer mechanistic insights and prioritize potential lead compounds, they remain predictive and necessitate future empirical confirmation. Overall, the study establishes a rigorous and academically grounded computational strategy that can guide subsequent efforts in the design of selective urease inhibitors for H. pylori –associated diseases.

Leishmaniasis is one of the infectious diseases caused by protozoa and is considered the second most significant parasitic disease after malaria. In this research, thiosemicarbazone Schiff base derivatives were synthesized via a one-pot, two-step, three-component reaction. Then, the effectiveness of the compounds against the two forms of Leishmania major and Leishmania tropica called amastigote and promastigote, was tested. All synthesized compounds displayed weak to good anti-amastigote and anti-promastigote activities. Notably, compounds 5g and 5p were the most potent compounds against amastigote and promastigote forms, respectively, of Leishmania major, with IC₅₀ = 26.7 µM and 12.77 µM. Analogues 5e and 5g were the most potent compounds against amastigote and promastigote forms of Leishmania tropica, with IC₅₀ = 92.3 µM and 12.77 µM, respectively. The cytotoxicity activity of the compounds was also evaluated using the J_774.A1 cell lines. Some of the screened derivatives displayed low cytotoxicity to macrophage infection. Among compounds, 5p and 5e showed the highest SI (95.4 and 34.6) against L. major and L. tropica, respectively. In the next phase, the most effective thiosemicarbazone derivatives were examined for their ability to induce apoptosis in promastigotes. According to the results, these compounds displayed different early and late apoptosis as well as necrotic effects on promastigotes of Leishmania major and Leishmania tropica. Furthermore, the compounds’ drug-likeness and pharmacokinetic parameters were predicted in silico. All compounds showed acceptable drug-likeness and pharmacokinetic profiles. Furthermore, the most likely sites of the compounds metabolized by the major cytochromes were identified. Additionally, the in silico compounds’ cardiotoxicity potential was assessed. This investigation showed compounds 5m-p were cardiotoxic. Lastly, molecular docking and molecular dynamics simulations were performed to explore the potential mechanisms of anti-leishmanial activity in the LmPRT1 active site.

A series of new benzylideneiminophenylthiazole analogues were designed and synthesized. Common spectroscopic methods, such as FT-IR, 1H-, 13C-NMR, and MASS spectra, and elemental analysis, were used to confirm the molecular structures. Then, the antioxidant, cytotoxicity, and anti-bacterial effects of synthesized analogues were assessed against 2,2-diphenyl-1-picrylhydrazyl (DPPH), three cancer cell lines, and two bacterial strains, respectively. Among the analogues, 7f was detected as the most potent compound for antioxidant activity. Moreover, the compounds 7b, 7f, and 7 g exhibited the maximum cytotoxicity activity against MCF-7, HepG-2, and A549 cell lines, respectively. Finally, 7e showed the highest anti-bacterial activity against both S. aureus and E. coli strains. It was concluded from the antioxidant, cytotoxicity, and anti-bacterial effects that the benzylideneiminophenylthiazoles might serve as candidate molecules for the development of small molecules with medicinal potential.

Stilbenes are a small family of polyphenolic secondary metabolites produced in a variety of closely related plant species. These compounds function as phytoalexins, aiding plant defense against phytopathogens and plants' adaptation to abiotic environmental factors. Structurally, some important phenolic compounds have a 14-carbon skeleton and usually have two isomeric forms, Z and E. Stilbenes contain two benzene rings linked by a molecule of ethanol or ethylene. Some derivatives of natural (poly)phenolic stilbenes such as resveratrol, pterostilbene, and combretastatin A-4 have shown various biological activities, such as anti-microbial, anti-cancer, and anti-inflammatory properties as well as protection against heart disease, Alzheimer's disease, and diabetes. Among stilbenes, resveratrol is certainly the most popular and extensively studied for its health properties. In recent years, an increasing number of stilbene compounds have been investigated for their bioactivity. This review focuses on the assessment of synthetic stilbene derivatives in terms of their biological activities and structure–activity relationship. The goal of this study is to consider the structural changes and different substitutions on phenyl rings that can improve the desired medicinal effects of stilbene-based compounds beyond the usual standards and subsequently discover biological activities by identifying effective alternatives of the evaluated compounds.

Leishmaniasis includes a range of parasitic diseases caused by numerous types of the protozoan kinetoplastid parasite. Fungal and bacterial pathogens have led to infectious illnesses causing some main public health problem in current years. A series of dihydropyridine and tetrahydropyrimidine derivatives having fluoro, bromo, and nitro substituents at para-phenyl ring on C4 of dihydropyridine and tetrahydropyrimidine rings were synthesized. Then, anti-leishmanial and antimicrobial potencies of compounds were assessed. All compounds were synthesized via Hantzsch and Biginelli reactions. All derivatives were evaluated for their anti-leishmanial and antimicrobial activities. Moreover, docking and molecular dynamics simulation calculations of the compounds in PRT1 binding site were performed to report the results of anti-leishmanial and antimicrobial activities. Compounds 4a and 4b showed the highest anti-amastigote and anti-promastigote activities. Compound 4a revealed the highest antimicrobial activity against E. coli, P. aeruginosa, and C. albicans strains. In addition, compound 4c showed the highest activity against S. aureus. The fluoro, bromo, and nitro substituents in para-position of phenyl group at C4 of dihydropyridine and tetrahydropyrimidine moieties as well as the bulk and length of the chain linking to the ester moieties are essential for anti-leishmanial and anti-microbial activities of these derivatives. Low cytotoxicity was shown by most of derivatives against macrophages. The molecular docking studies were in agreement with in vitro assay. Moreover, hydrogen binds, RMSF, RMSD, and Rg, strongly showed the steady binding of 4a and 4b compounds in PRT1 active site. Graphical abstract

Background: Alzheimer’s disease (AD) is an advanced and irreversible degenerative disease of the brain, recognized as the key reason for dementia among elderly people. The disease is related to the reduced level of acetylcholine (ACh) in the brain that interferes with memory, learning, emotional, and behavior responses. Deficits in cholinergic neurotransmission are responsible for the creation and progression of numerous neurochemical and neurological illnesses such as AD.Aim: Herein, focusing on the fact that benzylpyridinium salts mimic the structure of donepezil hydrochlorideas a FDA-approved drug in the treatment of AD, their synthetic approaches and inhibitory activity against cholinesterases (ChEs) were discussed. Also, molecular docking results and structure–activity relationship (SAR) as the most significant concept in drug design and development were considered to introduce potential lead compounds. Key scientific concepts: AChE plays a chief role in the end of nerve impulse transmission at the cholinergic synapses. In this respect, the inhibition of AChE has been recognized as a key factor in the treatment of AD, Parkinson’s disease, senile dementia, myasthenia gravis, and ataxia. A few drugs such as donepezil hydrochloride are prescribed for the improvement of cognitive dysfunction and memory loss caused by AD. Donepezil hydrochloride is a piperidine-containing compound, identified as a well-known member of the second generation of AChE inhibitors. It was established to treat AD when it was assumed that the disease is associated with a central cholinergic loss in the early 1980s. In this review, synthesis and anti-ChE activity of a library of benzylpyridinium salts were reported and discussed based on SAR studies looking for the most potent substituents and moieties, which are responsible for inducing the desired activity even more potent than donepezil. It was found that linking heterocyclic moieties to the benzylpyridinium salts leads to the potent ChE inhibitors. In this respect, this review focused on the recent reports on benzylpyridinium salts and addressed the structural features and SARs to get an in-depth understanding of the potential of this biologically improved scaffold in the drug discovery of AD.

The urease enzyme, a metalloenzyme having Ni²⁺ ions, is recognized in some bacteria, fungi, and plants. Particularly, it is vital to the progress of infections induced by pathogenic microbes, such as Proteus mirabilis and Helicobacter pylori. Herein, we reported the synthesis of a series of tetrahydropyrimidine derivatives and evaluated their antiurease activity. Finally, quantitative and qualitative analyses of the derivatives were performed via in silico studies. Urease inhibitory activity was determined as the reaction of H. pylori urease with different concentrations of compounds, and thiourea was used as a standard compound. Docking and dynamics methodologies were applied to study the interactions of the best compounds with the amino acids in the active site. All compounds showed good to excellent antiurease activity. The potent compounds were not cytotoxic against the HUVEC normal cell line. Based on the docking study, compound 4e with the highest urease inhibitory activity (IC₅₀ = 6.81 ± 1.42 µM) showed chelates with both Ni²⁺ ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC₅₀ = 8.45 ± 1.64 μM) in comparison to thiourea (IC₅₀ = 22.03 ± 1.24 μM). The molecular docking and dynamics simulation results were correlated with the in vitro assay results. Moreover, the derivatives 4a–n followed Lipinski's rule‐of‐five and had drug‐likeness properties.