Afshin Zarghi

Introduction: Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions. Methods: For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise. Results: Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders. Discussion: The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development. Conclusion: COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.

Background: Alzheimer disease (AD), first described by Alois Alzheimer more than a century ago, remains a major global health challenge. Glycogen synthase kinase-3β (GSK-3β) plays an important role in AD pathophysiology. Dysregulation of GSK-3β is associated with beta-amyloid accumulation, tau hyperphosphorylation, neurodegeneration, and cognitive impairment. Objectives: This study aimed to design and synthesize 17 arylalkyl urea derivatives as GSK-3β inhibitors and evaluate them in an animal model of AD. Methods: New arylalkyl derivatives were designed on the basis of the pharmacophores of GSK-3β inhibitors. Molecular docking and molecular dynamics simulations were used to evaluate the interactions of the designed compounds within the ATP-binding pocket of GSK-3β. The compounds were then synthesized by reacting substituted anilines with benzyl isocyanate, and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance spectroscopy, and liquid chromatography–mass spectrometry. The radial arm water maze was used to assess the effects of a selected compound on learning and memory deficits in an intracerebroventricular streptozotocin-induced rat model of sporadic Alzheimer-like disease. Results: Structure–activity relationship analysis indicated that variations in the R1 and R2 substituents played a crucial role in modulating GSK-3β inhibitory activity. Docking studies demonstrated that all novel derivatives fit well within the active site, with Val135 and Lys85 contributing prominently to ligand stabilization. On the basis of the docking results, compound 3b was selected for behavioural testing. Compound 3b significantly ameliorated spatial learning and memory deficits in a rat model of AD. Conclusions: Compound 3b emerged as a promising lead in this series, combining favorable GSK-3β binding properties with robust cognition-enhancing effects in vivo. These findings may inform therapeutic design, clinical translation, and strategic development in the evolving field of AD drug discovery.

Context: Poly(ADP-ribose) polymerase (PARP) is a key enzyme involved in DNA replication. Studies have shown that this enzyme plays a pivotal role in apoptosis and DNA damage repair. Excessive PARP activity, particularly that of PARP-1, may also lead to uncontrolled cellular growth and proliferation, thereby predisposing to tumor development. Similar effects have been observed with the overexpression of cyclooxygenase-2 (COX-2) in cancer development. In this review, our primary objective is to provide a concise and comprehensive structure–activity relationship to guide the design of compounds with dual inhibitory activity against PARP and COX-2. On the basis of this relationship, this review aims to support the development of novel compounds with potent inhibitory activity against PARP-1, as well as the design of dual PARP-1/COX-2 inhibitors. Evidence Acquisition: A comprehensive literature search was conducted to identify relevant studies on the design, synthesis, and biological evaluation of novel PARP and PARP-1 inhibitors, as well as dual-acting PARP-1/COX-2 inhibitors. Electronic databases, including Scopus, ScienceDirect, and Google Scholar, were systematically searched. Research articles published in English up to the most recent available date were considered. Studies were screened for relevance, clarity, and compliance with recognized molecular design guidelines. The collected information was analyzed and synthesized to provide an overview of the current state of PARP-1/COX-2 inhibitor synthesis approaches and design trends. Results: Based on the review findings, the use of PARP-1/COX-2 dual inhibitors may be considered a viable therapeutic approach for targeting two interconnected pathways involved in cancer development. Dual-acting agents provide an opportunity to enhance anticancer efficacy and reduce resistance to malignancy. Moreover, preclinical studies have demonstrated synergistic effects. Notably, there are substantial similarities between the SAR of single- and dual-acting PARP-1/COX-2 inhibitors. In addition, polycyclic core structures could be used to guide the design of these compounds. Furthermore, these polycyclic structures may exhibit other important antineoplastic properties, such as inhibition of topoisomerase II (TPO-II). Conclusions: In summary, to provide a more comprehensive review of the design and synthesis of novel chemical compounds as COX-2/PARP-1 dual inhibitors, additional compounds must be developed. Moreover, further clinical development and evaluation are required to improve their pharmacological properties and confirm their safety and efficacy in clinical settings.

Human immunodeficiency virus (HIV) infection remains a major global health concern, affecting nearly 40 million people worldwide. Therefore, discovering new therapeutic targets against HIV is still a continued demand. HIV integrase, an essential enzyme that mediates the integration of viral DNA into the host genome, represents a key target for antiretroviral therapy. HIV integrase inhibitors are mainly divided into two classes: integrase strand transfer inhibitors (INSTIs), which act on the enzyme's active site, and allosteric integrase inhibitors (ALLINIs), which bind to a distinct site formed through interaction with the host protein lens epithelium‐derived growth factor p75 (LEDGF/p75). LEDGF/p75 is a host cellular cofactor that plays a pivotal role in regulating integrase function. This review examines the structure and functional importance of LEDGF/p75 in HIV‐1 integrase activity, alongside the development and progress of inhibitors targeting the integrase‐LEDGF/p75 interaction.

Background: Cancer is regarded as one of the most significant health concerns in the world. Hepatocellular carcinoma (HCC) is a malignancy with high incidence and mortality rates and can lead to death. Cyclooxygenase (COX)-2 is responsible for the development of various cancers, including HCC. Therefore, the use of COX-2 inhibitors can help in the prevention and treatment of cancer. Objectives: The present study aimed to synthesize and examine the effect of imidazolium [1,2-a] piperidinium (4cl-A) and benzo [d] imidazo [1,2-b] thiazolium (1-naphtyl-C) compounds as COX-2 inhibitors on the rat model of HCC. Methods: Animals were randomly assigned to control and HCC induction groups. The study duration was 15 weeks. The HCC was induced using DEN (200 mg/kg, ip) at a single dose and 2-AAF (dietary, 0.02% w/w, for 2 weeks). After 15 weeks, the investigation focused on mitochondrial toxicity parameters. One-way and two-way ANOVA statistical tests were used to analyze the data. Results: The results showed that 4cl-A and 1-naphtyl-C can reduce mitochondrial activity, increase the level of free radicals (ROS), collapse in mitochondrial membrane potential (MMP), cause swelling of mitochondria, and release cytochrome c from HCC mitochondria. While this effect was not observed in healthy mitochondria. Conclusions: The results of the study indicate that these COX-2 inhibitors, along with selected drugs, can help in the treatment of HCC. However, more clinical studies should be conducted.

Zizyphus jujuba is a thorny Rhamnaceous plant found throughout Europe and Southeast Asia. It possesses medicinal properties and is utilized in traditional medicine. Frankincense is recognized for its analgesic properties. The purpose of this study was to determine the anti-nociceptive efficacy of Z. jujuba and Frankincense in assessing their effect on pain associated with knee osteoarthritis. This research included 46 people ranging in age from 50 to 70 years. They were placed into two groups: test and control. Z. jujuba and Frankincense pills were made, and participants were given a Persian-validated Western Ontario and McMaster Universities (WOMAC), and visual analogue score (VAS) questionnaire. The variables were evaluated before and after the intervention. In the test group, there was a considerable decrease in pain VAS score following the administration of dosages of Z. jujuba/Frankincense pills. The analgesic efficacy of the aforementioned herbal medicines under study was significant after taking mixed jujube/frankincense/aloe vera tablets at doses of 250 mg/100 mg/25 mg, respectively. The combined standardized mean difference for the WOMAC, were 14.56 ± 3.2, 13.9 ± 3.50, and 13.33 ± 4.09, for the before, one-week, and one-month follow-ups, respectively. WOMAC and VAS scores were different between “before intervention” as well as both “one week”, and “one-month” follow-ups. In summary, pain reduced in study group compared to their respective baseline (VAS and WOMAC outcome measures). These findings confirmed that Z. jujube, and frankincense supplementation effectively reduce pain and improve functional outcomes in OA patients, supporting their use as a complementary treatment alongside standard therapies.

: Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can contribute to cardiac fibrosis, heart failure, and various cancers by upregulating the COX-2/PGE2 axis. Therefore, suppressing COX activity has emerged as a potentially effective treatment for chronic inflammatory disorders and cancer. This review explores the mechanisms of TNF-α-induced COX-2/PGE2 expression, a significant pathophysiological feature of cancer development. Furthermore, we summarize chemical compounds with dual COX-2/TNF-α inhibitory actions, providing an overview of their structure-activity relationship. These insights may contribute to the development of new generations of dual-acting COX-2/TNF-α inhibitors with enhanced efficacy.

Background: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. Objectives: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. Methods: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. Results: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 μM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 μM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. Conclusion: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Background: The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes. Objective: The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores. Method: A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs). Results: Most of the synthesized analogs were found to be moderately active against the virus, with EC50 values ranging from 40 to 140 μM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC50 > 500 μΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC50 values of 40 and 45 μΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg2+ coordination might be the possible mechanism of the anti-viral activity. Conclusion: Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.