Drug Development Research[JOURNAL]
Sun
200 papers
Benzimidazole-Based VEGFR-2 Inhibitors Inspired by Sorafenib: Synthesis, Biological Evaluation, and Mechanistic Insights.
Dewidar MA, Allam HA, Abdel-Aziz HA … +2 more , Elnagar MR, Ibrahim NM
Drug Dev Res · 2026 Aug · PMID 42381467 · Publisher ↗
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based deri...
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based derivatives (3a-k, 5a-d, 8a-g, and 10a-d) were rationally designed to incorporate the essential structural and pharmacophoric features required for effective VEGFR-2 inhibition, followed by their synthesis and biological evaluation. In vitro kinase assays demonstrated that the synthesized derivatives inhibited VEGFR-2 with IC values ranging from 0.061 to 1.895 µM. Based on their enzymatic potency, the most active compounds (3f, 3h, 3j, 8d, and 8g) were further investigated for antiproliferative activity against HUVEC, MCF-7, and HepG2 cell lines. Among them, Compound 3f exhibited IC values of 13.34, 5.32, and 5.02 µM, respectively, showing activity comparable to sorafenib. Evaluation against normal MCF-10A and Vero cell lines indicated favorable biocompatibility and a reasonable selectivity profile. Mechanistic studies revealed that 3f induced G2/M-phase arrest, promoted apoptosis, and suppressed cell migration, accompanied by a reduction in VEGFR-2 protein expression levels. Molecular docking suggested that the synthesized derivatives adopt a binding mode consistent with Type II VEGFR-2 inhibitors, while in silico ADME and toxicity predictions supported an acceptable toxicity profile and drug-like characteristics.
Luliconazole Potentiates Efficacy of Miltefosine Against Leishmania donovani.
Singh N, Rani M, Mandal HP … +4 more , Yadav R, Bhat AH, Alti D, Singh SK
Drug Dev Res · 2026 Aug · PMID 42345507 · Publisher ↗
Visceral leishmaniasis is a vector-mediated parasitic disease caused by Leishmania donovani. Its treatment relies on chemotherapy with limited options. Existing drugs face significant challenges, including low efficacy,...
Visceral leishmaniasis is a vector-mediated parasitic disease caused by Leishmania donovani. Its treatment relies on chemotherapy with limited options. Existing drugs face significant challenges, including low efficacy, high relapse rates, toxicity, and cost. Therefore, exploring novel chemotherapeutic strategies identified as newer drugs targeting L. donovani CYP51 either alone or in combination with Miltefosine, which presents a promising alternative to current therapy. Here, we have evaluated the antileishmanial potential of an azole drug, luliconazole, which was previously demonstrated to target the sterol biosynthesis pathway in Leishmania major, in combination with conventional antileishmanial agents. Luliconazole exhibited significant inhibitory activity against both extracellular and intracellular L. donovani, with half-maximal inhibitory concentrations of 4.67 and 6.24 µM, respectively. Notably, the addition of miltefosine and luliconazole combinations resulted in a synergistic effect, reducing the effective doses by 3.26- and 5.62-fold compared to monotherapy with miltefosine and luliconazole, respectively. Conversely, the combination of luliconazole with Amphotericin B yielded antagonistic effects. A significant increase in nitric oxide by the parasite-infected macrophages after luliconazole treatment underscores its leishmanicidal potential. Evaluation of host cell cytotoxicity, hemolytic assays, and oxidative burst affirmed the safety of luliconazole. This study is limited to in vitro intracellular amastigote. These findings highlight the efficacy of luliconazole, particularly in combination with miltefosine. Further investigations including formulation development and in vivo validation, are needed to assess the translational potential. This is the first study to demonstrate that luliconazole enhances miltefosine efficacy against L. donovani.
Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
Ugale V, Sharon N, Salunkhe C … +5 more , Salunkhe J, Lokwani D, Patil K, Reddy PN, Kulkarni P
Drug Dev Res · 2026 Aug · PMID 42324842 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-c...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC = 1.08 µM; BuChE, IC = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.
Identification of Sulfonamide-Based Thiazolidine-2,4-Dione Derivatives as VEGFR-2 and Tumor-Associated hCA IX Inhibitors With Hypoxia-Targeted Anti-Colorectal Cancer Activity.
Tawfik HO, Dahab MA, Elnagar MR … +8 more , Ammara A, Elkotamy MS, Abdulla MH, Al-Khayal K, Fares M, Nocentini A, Supuran CT, Eldehna WM
Drug Dev Res · 2026 Aug · PMID 42324832 · Publisher ↗
Given their critical roles in tumor progression and hypoxia adaptation, concurrent inhibition of carbonic anhydrase IX (hCA IX) and vascular endothelial growth factor receptor-2 (VEGFR-2) is a viable therapeutic approach...
Given their critical roles in tumor progression and hypoxia adaptation, concurrent inhibition of carbonic anhydrase IX (hCA IX) and vascular endothelial growth factor receptor-2 (VEGFR-2) is a viable therapeutic approach. This study rationally developed, synthesized, and biologically assessed a novel class of thiazolidinedione-benzenesulfonamide hybrids as possible dual hCA IX/VEGFR-2 inhibitors. A number of agents, including 4a, 4b, 4e, 4g, 6a, and 6b, showed strong hCA IX inhibition (K = 15.0-37.9 nM), outperforming the reference inhibitor acetazolamide (K = 25 nM) and displaying better selectivity indices. Moreover, these substances efficiently suppressed VEGFR-2, with IC values ranging from 0.055 to 1.080 µM. Under both normoxic and hypoxic conditions, biological evaluation demonstrated strong anti-proliferative activity against colorectal cancer cell lines (HT-29 and HCT-116). Compound 4g stood out as the most promising candidate among the investigated derivatives, showing greater activity to 5-fluorouracil during hypoxia and comparable potency under normoxia (IC = 5.89 vs. 26.66 µM). In hypoxic conditions, 4g significantly enhanced the cytotoxicity of 5-fluorouracil, increasing its activity by more than sevenfold. 4g caused cell-cycle arrest at the G/G/M phases, raised pro-apoptotic markers (caspase-3, caspase-9, and BAX), downregulated the anti-apoptotic protein Bcl-2, and dramatically enhanced apoptotic cell death (total apoptosis: 37.78%), according to mechanistic studies. The persistent binding of 4g inside the zinc-containing active site of hCA IX and the ATP-binding pocket of VEGFR-2 was validated by molecular docking and molecular dynamics simulations. Additionally, favorable pharmacokinetic and drug-likeness features were shown by in silico ADME research. All of these results point to compound 4g as a promising mechanism-based dual VEGFR-2/hCA IX inhibitor with strong anti-colorectal cancer action, especially in hypoxic tumor microenvironment circumstances.
Bacterial mRNA Vaccines: Programming Immunity Against Antimicrobial Resistance.
Liao R, Luo M, Yang F … +10 more , Xu L, Zhang J, Zhang W, Guan S, Zhang Y, Luo P, Cheng P, Yang J, Li Y, Wang Q
Drug Dev Res · 2026 Aug · PMID 42318873 · Full text
The relentless rise of antimicrobial resistance poses a critical threat to global health, urgently demanding the development of antibacterial vaccines. Messenger RNA (mRNA) technology, validated during the COVID-19 pande...
The relentless rise of antimicrobial resistance poses a critical threat to global health, urgently demanding the development of antibacterial vaccines. Messenger RNA (mRNA) technology, validated during the COVID-19 pandemic, offers a powerful platform of fast development and flexibility. However, its application against bacterial pathogens remains an emerging frontier due to the structural complexity of bacterial antigens, challenges in achieving effective mucosal and cellular delivery, and the need to elicit balanced Th1/Th17-dominated immune responses for durable protection. Progress in antigen design, mRNA engineering, and lipid nanoparticle (LNP) delivery has enabled early preclinical success against Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Streptococcus pneumoniae. Yet, challenges such as complex antigen expression, mucosal targeting, and immune durability persist. This review provides a brief overview of recent advances in bacterial mRNA vaccine design, including antigen selection, mRNA engineering, and delivery platform optimization. Additionally, we summarize current preclinical progress across key bacterial pathogens and highlight emerging strategies that integrate AI-guided antigen discovery, synthetic biology, and next-generation delivery systems to accelerate clinical translation. Finally, we highlight the prospects of bacterial mRNA vaccines by integrating synthetic biology, AI-driven antigen prediction, and advanced delivery systems. These cutting-edge technologies hold the promise of overcoming existing barriers, ultimately establishing mRNA vaccines as a viable and powerful strategy to curb the tide of antibiotic-resistant infections.
Identification of Quinoline Tethered Thiadiazole/Thiazole Derivatives as Potent Tyrosinase Inhibitors With Promising Anti-Toxoplasma gondii Agents: Design, Synthesis, and Computational Analysis.
Sabt A, Chyb M, Srour AM … +8 more , Bekier A, Farag H, Shaldam MA, Ibrahim HAA, Saleh A, Gatkowska J, Rashdan HRM, Dziadek J
Drug Dev Res · 2026 Aug · PMID 42311211 · Publisher ↗
Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, remains a serious global health concern, largely because current treatments with sulfonamides and pyrimethamine are toxic and increasingly ineffective du...
Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, remains a serious global health concern, largely because current treatments with sulfonamides and pyrimethamine are toxic and increasingly ineffective due to rising drug resistance. In response, this study describes the design, synthesis, and laboratory evaluation of novel hybrid molecules that merge a quinoline backbone with either thiadiazole (compounds 8a-e) or thiazole (compounds 12a-d) bioactive groups to develop safer and more effective therapies. Cytotoxicity tests on mouse (L929) and human (Hs27) fibroblast cell lines revealed distinct safety profiles: the thiadiazole hybrids (8a-e) were significantly toxic to host cells, whereas the thiazole-based versions (12a-d) were much safer, with several showing no toxicity even at 250 µg/mL. When tested against T. gondii, the quinoline-thiazole hybrids proved the most effective. Notably, 12b and 12c achieved IC values of 0.40 and 0.52 µg/mL, respectively, better than the reference drug pyrimethamine (IC = 0.74 µg/mL). Compound 12c emerged as the top candidate, with an excellent selectivity index (SI) of 71.0 in human Hs27 cells. Further mechanistic work showed that 12c strongly inhibits tyrosinase, a potential parasitic target. Kinetic studies revealed a mixed-type inhibition mechanism, with an IC of approximately 5 µM, 10 times more potent than kojic acid (48 µM), a standard inhibitor. Molecular docking and dynamics simulations confirmed stable binding between 12c and tyrosinase. Together, these findings underscore the therapeutic promise of the quinoline-thiazole scaffold, particularly compound 12c, as a lead for developing targeted, low-toxicity anti-toxoplasmosis drugs. The results are expected to expand the existing toolkit of small molecules targeting the parasite and reinforce the importance of molecular hybridization in drug development. Additional research is needed to clarify how these compounds work and to assess their effectiveness in living organisms in order to fully unlock their potential as anti-parasitic drugs.
Selenium-Containing 1,4-Naphthoquinone Derivatives Trigger Reactive Oxygen Species and Apoptosis in Triple-Negative Breast Cancer Cells.
Angulo-Elizari E, Raza A, Johnson H … +5 more , Martínez-Sáez N, Encío I, Sharma AK, Sanmartín C, Plano D
Drug Dev Res · 2026 Aug · PMID 42311206 · Full text
Cancer ranks as a leading cause of death worldwide, demanding new affordable therapies. Nature offers a diverse array of bioactive scaffolds, including 1,4-naphthoquinone, which serves as a precursor for numerous natural...
Cancer ranks as a leading cause of death worldwide, demanding new affordable therapies. Nature offers a diverse array of bioactive scaffolds, including 1,4-naphthoquinone, which serves as a precursor for numerous natural and synthetic compounds with potent antitumor properties. Selenium, an essential trace element, has shown significant potential in medicinal chemistry when incorporated into organic molecules. In this study, we synthesized 24 novel selenium-containing derivatives based on menadione (series A) and 1,4-naphthoquinone (series B), incorporating selenium as selenoester and selenocyanate functionalities. Initial cytotoxic screening at 25 and 10 µM against four cancer cell lines (MDA-MB-231, PC-3, HTB-54 and HCT-116) identified five active compounds, with B2 and B8 exhibiting the highest potency and selectivity against breast cancer cells. Further biological evaluation via the NCI Developmental Therapeutics Program confirmed their apoptosis induction and antiproliferative activity through reactive oxygen species (ROS) production. Molecular dynamics simulations additionally suggest that B2 and B8 may act as topoisomerase II alpha inhibitors. These results position compounds B2 and B8 as promising candidates for breast cancer therapy, paving the way for further investigation into their potential as chemotherapeutic agents.
A Medicinal Chemistry Perspective on Anticonvulsant Drug Design: Targets, Mechanisms, and Spiro Compounds.
Hamid GA, Elmasry GF, El-Moghazy SM … +1 more , Abd-Allah WH
Drug Dev Res · 2026 Jun · PMID 42299108 · Publisher ↗
The neurological condition known as epilepsy is typified by frequent, unprovoked seizures brought on by aberrant or excessive synchronized neuronal activity in the brain. It can arise from various causes, including brain...
The neurological condition known as epilepsy is typified by frequent, unprovoked seizures brought on by aberrant or excessive synchronized neuronal activity in the brain. It can arise from various causes, including brain injury, tumors, infections, immune disorders, or congenital anomalies. However, in many patients, the underlying cause remains unknown. Epileptic seizures are broadly classified into two types: generalized and focal (or partial) seizures. Generalized seizures involve electrical discharges that affect the entire brain, while focal seizures are confined to a specific region. The World Health Organization (WHO) estimates that 50 million individuals worldwide suffer from epilepsy, with low- and middle-income nations accounting for over 80% of cases. In spite of the development of numerous antiepileptic drugs (AEDs), about 30% of individuals with epilepsy suffer from drug-resistant epilepsy (DRE), where seizures remain uncontrolled by current treatments. As a result, the search for new anticonvulsants with improved efficacy and reduced toxicity is a paramount demand. However, target-based drug discovery approaches are relatively uncommon due to limited understanding of the molecular pathways involved in epilepsy and the complex mechanisms of action of most existing AEDs. In this review, we investigate the characteristics of anticonvulsant drugs, the classification of epileptic seizures, the mechanisms through which these drugs exert their effects and spiro compounds with anticonvulsant activity.
Structure-Based Identification and Synthesis of Benzimidazole Azo-Schiff Base Derivatives as Recommended CK2 and PIM-1 Inhibitors.
Hassan HF, Eissa ME, Hussein MS … +8 more , Al-Qazzan MB, Al-Akeedi M, Goda MN, Al-Tameemi SJ, Abed HN, Ibraheem TK, Yousef TA, Al-Karmalawy AA
Drug Dev Res · 2026 Jun · PMID 42290024 · Publisher ↗
Casein Kinase-2 (CK2) and Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) are kinases that are continuously active and work together to promote oncogenesis, thus becoming an important target for ant...
Casein Kinase-2 (CK2) and Proviral Integration site for Moloney murine leukemia virus-1 (PIM-1) are kinases that are continuously active and work together to promote oncogenesis, thus becoming an important target for anti-cancer drugs. This research highlights the design, synthesis, and in silico evaluation of a new class of azo-Schiff bases bearing benzimidazole moieties (A1-A7) as potential dual inhibitors of CK2/PIM-1 targets. The compounds were synthesized using diazotization/azocoupling reaction and Schiff's base condensation reactions, where structural elucidation was accomplished through FT-IR, 1H NMR, and 13C NMR analyses. The molecular docking process was performed using the GOLD docking program against ATP-binding sites on CK2 (PDB: 4DTK) and PIM-1 (PDB: 4KWP), followed by MD simulation for 100 ns using GROMACS software. Through computational screening, molecules A4 and A6 were found to be the most potent dual inhibitors. Compound A6 displayed the greatest affinity to CK2 with a PLP fitness value of 81.33, whereas compound A4 displayed the highest affinity to PIM-1 with a PLP fitness value of 86.80. The interesting thing is that both compounds revealed very good cross-reactivity to both enzymes and were superior to other compounds in the series concerning dual-target PLP fitness. The MD simulation results showed that A4 and A6 exhibit high stability in their interactions with minimal structural fluctuations, attributed to hydrogen bonds formed consistently within the active site regions. In contrast, A7 has been shown to be a PIM-1 selective inhibitor. The attachment of azo-Schiff base groups to the benzimidazole core results in an interesting structure with a potential for multi-kinase inhibitory activity. The current study has identified molecules A4 and A6 as potential leads that require further in vitro and in vivo validation.
Harnessing the Ocean's Power: Fucoidan as a Novel Neuroregenerative Agent.
Wu Q, Hui X, Cui A … +1 more , Meng X
Drug Dev Res · 2026 Jun · PMID 42266137 · Publisher ↗
Neurological disorders, characterized by progressive neuronal loss and functional decline, pose a formidable challenge to global health due to the lack of effective therapies. Fucoidan, a class of fucose-rich sulfated po...
Neurological disorders, characterized by progressive neuronal loss and functional decline, pose a formidable challenge to global health due to the lack of effective therapies. Fucoidan, a class of fucose-rich sulfated polysaccharides derived from brown seaweed, has emerged as a highly promising candidate for neuronal regeneration. This review synthesizes the extensive body of preclinical evidence supporting the neuroprotective and neuroregenerative potential of fucoidan. Its therapeutic efficacy relies on potent anti-inflammatory activity through the modulation of glial cell activation, significant antioxidant effects by neutralizing reactive oxygen species and reinforcing endogenous defenses, and direct anti-apoptotic actions that inhibit programmed cell death. Furthermore, this review highlights the pivotal and emerging role of the microbiota-gut-brain axis as a key regulator of the neuroprotective effects of fucoidan, whereby its prebiotic activity in the gut instigates systemic benefits that extend to the central nervous system. By consolidating findings from diverse preclinical models of ischemic stroke, traumatic brain injury, Alzheimer's disease, and Parkinson's disease, we conclude that fucoidan is a powerful, multitarget agent. Future research focused on establishing precise structure-activity relationships and further elucidating its action via the gut-brain axis will be important for translating this promising natural compound into a validated clinical therapy for neurological disorders.
Entacapone Ameliorates MASLD by Inhibiting FTO Demethylase Activity.
Giri S, Sharma D, Kumar V
Drug Dev Res · 2026 Jun · PMID 42262646 · Publisher ↗
MASLD is a chronic liver disease characterized by excess fat build up in the liver. Elevated expression of FTO has been implicated in steatosis and MASLD development. There is no standard treatment for MASLD. Here we inv...
MASLD is a chronic liver disease characterized by excess fat build up in the liver. Elevated expression of FTO has been implicated in steatosis and MASLD development. There is no standard treatment for MASLD. Here we investigated the hepatoprotective effects of entacapone-a pharmacological inhibitor of FTO-in preclinical models. Entacapone was administered intra-peritoneally at a daily dose of 10 or 30 mg in a MASLD mouse model. Changes in obesity, lipid accumulation and liver fibrosis were monitored during the treatment period. Biomarkers of hepatic and metabolic functions were measured by bioanalyzer. The FTO and metabolic gene transcripts were quantitated by RT-qPCR whereas the m6A levels were measured by ELISA. The hepatic expression of FTO protein in mice and clinical samples (MASLD, MASH and cirrhosis) was visualized by immunohistochemical staining. The regulation of FTO gene by entacapone was also investigated in cell culture. Treatment of mice with entacapone led to a significant reduction in obesity and hepatic fat build-up as well as normalization of metabolic functions and MAS score. The m6A levels in gene transcripts were high and coincided with reduced expression of FTO, lipogenic and inflammatory genes. Interestingly, FTO isoforms FTO-1 FTO-5 and FTO-12 were overexpressed in the MASLD patients whereas no change in FTO-5 and FTO-12 levels was observed in MASH and cirrhosis patients. Further, FTO expression was down-regulated by entacapone in immortalized hepatocytes. This study highlights the therapeutic potential of entacapone in the management of metabolic liver disease by targeting the FTO demethylase activity.
Tramiprosate, the Active Agent of ALZ-801, Modulates Amyloidogenic APP Processing and Tau Phosphorylation in a Cellular Model of Alzheimer's Disease.
Biberoglu K, Tacal O
Drug Dev Res · 2026 Jun · PMID 42237659 · Publisher ↗
ALZ-801, a valine-conjugated prodrug of tramiprosate, has recently been evaluated in a Phase III trial as a potential Alzheimer's disease (AD)-modifying therapy. Tramiprosate reduces misfolding of amyloid beta (Aβ) monom...
ALZ-801, a valine-conjugated prodrug of tramiprosate, has recently been evaluated in a Phase III trial as a potential Alzheimer's disease (AD)-modifying therapy. Tramiprosate reduces misfolding of amyloid beta (Aβ) monomers and inhibits oligomer formation. In the present study, we investigated tramiprosate's effects on amyloidogenic processing of amyloid precursor protein (APP) and tau phosphorylation using the N2a-APPSwe cell line as a cellular model of AD. Tramiprosate decreased levels of secreted Aβ40 and Aβ42 in a dose-dependent manner without affecting cell viability. It also reduced the levels of APP, β-site APP cleaving enzyme 1 (BACE1), and presenilin 1 C-terminal fragment (PS1-CTF) in this cellular model, indicating that tramiprosate may modulate amyloidogenic APP processing at multiple steps, thereby reducing Aβ production. Additionally, tramiprosate decreased tau phosphorylation at Ser202/Thr205 and Ser396/Ser404 in a dose-dependent manner while total tau level remained unchanged. Increased phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, without altering total GSK-3β levels, suggests that GSK-3β inhibition underlies the decrease in tau phosphorylation at these sites. As a result, tramiprosate's impact on both amyloidogenic APP processing and tau phosphorylation reveals its potential to modify AD.
New Treatment Approach Using Peptoid-Based Vaccines in Parkinson's Disease.
Ekrani ST, Faraj TA, Taha CH … +1 more , Esmaeili SA
Drug Dev Res · 2026 Jun · PMID 42224407 · Publisher ↗
As the population ages, the prevalence of neurodegenerative disease, such as Parkinson's disease (PD) continues to grow and new and alternative treatment modalities will be required to deal with these issues. Peptoids ar...
As the population ages, the prevalence of neurodegenerative disease, such as Parkinson's disease (PD) continues to grow and new and alternative treatment modalities will be required to deal with these issues. Peptoids are oligomers of N-substituted glycine. These peptidomimetics molecules provide many advantages over peptide-based vaccines. Unlike peptides, peptoids are resistant to proteolytic degradation, and allow peptoids to retain therapeutic potential in some difficult physiological environments. Such molecules can also be engineered for structural stability and biomarker detection. All these elements make them suitable for a variety of applications in PD. Current research has investigated their potential to prevent protein aggregation, modulate cell signaling pathways and as anti-inflammatory agent for neuroprotective therapy. Expanding our understanding and applications of peptoids has great potential hope for future treatment options beyond current neurodegenerative disease options. This review will summarize the various applications peptoids, role in vaccination, potential for developing better prevention and treatment for PD.
Unveiling Remyelinating Properties of Roflumilast in CPZ-Induced Neuronal Demyelination in Mice.
Kamel AS, Sameh I, Khattab MA … +4 more , El-Sahar AE, Zaki HF, Badary OA, Farrag SM
Drug Dev Res · 2026 Jun · PMID 42207934 · Publisher ↗
Multiple sclerosis (MS) is a demyelinating disorder characterized by oligodendrocyte apoptosis, microglial activation at demyelination sites, with ROS production. These pathological processes are closely associated with...
Multiple sclerosis (MS) is a demyelinating disorder characterized by oligodendrocyte apoptosis, microglial activation at demyelination sites, with ROS production. These pathological processes are closely associated with phosphodiesterase-4 (PDE-4) activity. Roflumilast (ROFL), a selective PDE-4 inhibitor, has demonstrated neuroprotective effects in various central nervous system disorders. However, its specific role in MS pathogenesis remains to be fully elucidated. This study aims to investigate the effects of ROFL on oligodendrocyte maturation, microglial polarization and the impact on protein kinase A/cAMP-response element binding protein pathway. An MS model was induced in mice via dietary administration of cuprizone (CPZ) for 7 days, starting with 0.7% (w/w), followed by 0.2% for 5 weeks. Beginning in week 5, mice received ROFL (5 mg/kg/day, p.o) for 2 weeks. ROFL improved the motor abnormalities in the rotarod and open field tests. Together, ROFL downregulated the PDE4/cAMP-dependent pathway, exerting anti-inflammatory effects by suppressing NF-κB and TNF-α. Additionally, microglial polarization shifted toward the anti-inflammatory M2 phenotype, with CD163 increment, in contrast to the pro-inflammatory M1 marker CD83. Furthermore, ROFL's antioxidant capacity was evidenced by reduced malondialdehyde levels, replenishment of glutathione levels, and reduced phosphorylation of ERK1/2. Oligodendrocyte differentiation and maturation were enhanced, as indicated by elevated levels of proteolipid protein, myelin-associated glycoprotein, CNPase, and myelin basic protein. Remyelination was confirmed through Luxol fast blue staining, accompanied by reduced apoptotic marker, caspase-3, in oligodendrocytes. Collectively, these findings suggest that ROFL exerts neuroprotective effects and highlight the therapeutic potential of PDE-4 inhibition as a strategy for MS treatment.
Molecular Boomerangs Against Cancer: Design, Synthesis, Biological Evaluation, and In Silico Study of Novel Dual PARP-1/EGFR Inhibitors.
Tawfik HO, Tayel A, Hefny SM … +8 more , Al-Warhi T, Sedky NK, El-Hamaky AA, Khattab NA, Farouk AKBAW, Shaldam MA, Eldehna WM, Nafie MS
Drug Dev Res · 2026 Jun · PMID 42207930 · Publisher ↗
A possible method for improving anti-cancer efficacy is the combination of the inhibition of epidermal growth factor receptor (EGFR) and poly (ADP-ribose) polymerase-1 (PARP-1). This work describes the rational design, s...
A possible method for improving anti-cancer efficacy is the combination of the inhibition of epidermal growth factor receptor (EGFR) and poly (ADP-ribose) polymerase-1 (PARP-1). This work describes the rational design, synthesis, and complete characterization of a novel class of boomerang-shaped dual PARP-1/EGFR inhibitors (3a-o). HepG-2 and MDA-MB-231 cancer cell lines were used to test the synthesized compounds' antiproliferative potential; MDA-MB-231 cells showed greater sensitivity. Compounds 3h, 3i, and 3j had the strongest cytotoxic effects among the series, with IC values of 0.23, 0.90, and 1.40 µM, respectively, against MDA-MB-231 cells. Compared with the reference medications erlotinib and olaparib, compound 3h showed the highest dual inhibition (EGFR IC = 1.62 µM and PARP-1 IC = 0.36 µM) in enzymatic experiments, demonstrating that these compounds effectively inhibited both EGFR and PARP-1. Compound 3h strongly promoted apoptosis in MDA-MB-231 cells, increasing the total apoptotic population to 20.04% and causing G1-phase cell-cycle arrest, as determined by mechanistic studies. In vivo tumor growth inhibition trials showed a tumor inhibition rate (TIR%) of 41.4% for compound 3h compared to 48.8% for doxorubicin (DOX). Liver function biomarkers and hematological parameters remained within the acceptable levels following compound 3h treatment. The dual-target activity of compound 3h was further validated by molecular docking and molecular dynamics simulations, which demonstrated persistent binding contacts within the active sites of PARP-1 and EGFR.
Lead Discovery via Scaffold Refinement: Structure-Guided Optimization of 1,2,4-Triazolo[1,5-a]Pyrimidines as Potent Dual EGFR/CDK-2 Inhibitors Targeting Colorectal Carcinoma.
Nasr R, Haffez H, Nafie MS … +3 more , Moustafa MAA, El-Kerdawy MM, Ali AR
Drug Dev Res · 2026 Jun · PMID 42200498 · Publisher ↗
A unique series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed and synthesized as potential dual inhibitors of EGFR and CDK-2 to circumvent drug resistance in colorectal cancer patients through multi-targete...
A unique series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed and synthesized as potential dual inhibitors of EGFR and CDK-2 to circumvent drug resistance in colorectal cancer patients through multi-targeted therapy. When tested against HCT-116 colorectal carcinoma cells, these compounds showed anticancer activity with lower toxicity against normal cells, thus providing a high selectivity index (> 2). Leads 12c, 12i, and 22 demonstrated potent kinase inhibition, with 22 yielding a CDK-2 IC₅₀ of 0.03 µM (seliciclib: 0.02 µM), and 12c delivering an EGFR IC₅₀ of 0.12 µM (erlotinib: 0.01 µM). These leads induced G/M cell cycle arrest and apoptosis in HCT-116 cells via upregulation of Bax, cytochrome c, and caspase-3, and downregulation of VEGF, AKT-1, and Bcl-2. Network pharmacology suggested EGFR and CDK-2 as key targets. Redocking reference ligands erlotinib (EGFR, PDB: 1M17) and seliciclib (CDK-2, PDB: 2A4L) confirmed docking poses, and binding interactions of 12c and 22 matched those of references. Using 100-ns molecular dynamics simulations proved the stability of ligand-protein complexes and further supported the reliability of predicted binding modes. Promising ADMET profiles and good drug likeness are evident in these leads. These data underscore the great potential of this scaffold for developing dual EGF/CDK-2 inhibitors aimed at resistance mechanisms in more aggressive cancers and can thus be pursued further in preclinical optimization.
Discovery of Novel 5-Substituted-4-Allyl-1,2,4-Triazoles as Potential Nonsteroidal Anti-Inflammatory Agents via Downregulation of iNOS Expression.
Abbas SH, Hammad ASA, El-Kossi DMMH … +1 more , Ali TFS
Drug Dev Res · 2026 Jun · PMID 42188256 · Publisher ↗
Inducible nitric oxide synthase (iNOS) is a key mediator of inflammatory signaling, and excessive iNOS-derived nitric oxide (NO) contributes to the pathology of multiple chronic inflammatory disorders. Herein, we report...
Inducible nitric oxide synthase (iNOS) is a key mediator of inflammatory signaling, and excessive iNOS-derived nitric oxide (NO) contributes to the pathology of multiple chronic inflammatory disorders. Herein, we report the design and synthesis of a focused series of 5-substituted 4-allyl-1,2,4-triazole-3-thiol derivatives (7a-f) bearing an acetanilide fragment, targeting suppression of iNOS-driven NO production. In lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, several analogues attenuated nitrite accumulation, with compound 7c emerging as the most active member of the series (80% inhibition at 100 μM; IC₅₀ = 12.91 μM). Mechanistically, 7c downregulated iNOS protein expression in a concentration-dependent manner, consistent with its NO-suppressing phenotype. In vivo, compound 7c significantly reduced L-arginine-potentiated carrageenan paw edema, decreased paw nitrite levels, improved histopathological inflammatory features, and displayed lower ulcerogenic liability than indomethacin at the tested conditions. Collectively, these findings identify allyl-1,2,4-triazoles as a promising scaffold for developing next-generation anti-inflammatory agents acting through iNOS downregulation.
Sustainable One-Pot Synthesis of Novel Triazolopyrimidine Derivatives as Selective CDK4 Inhibitors for Breast Cancer Therapy.
Elsayed DA, Shehab WS, Mohamed MM … +6 more , Mesbah AE, El-Bassyouni GT, Mousa SM, Abo Elenin OM, Assy MG, Tantawy ES
Drug Dev Res · 2026 Jun · PMID 42187623 · Publisher ↗
A sustainable and effective one-pot synthesis of new 4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile derivatives was accomplished using Mn₃O₄ nanoparticles as a recyclable nanocatalyst under moderate and envi...
A sustainable and effective one-pot synthesis of new 4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile derivatives was accomplished using Mn₃O₄ nanoparticles as a recyclable nanocatalyst under moderate and environmentally benign conditions. The approach provided outstanding yields and adheres to sustainable chemical principles. Analysis revealed CDK4 as a possible therapeutic target linked to breast cancer growth, therefore elucidating its biological potential. In silico molecular docking validated the robust binding affinities of the synthesized derivatives to the CDK4 active site, especially compound 4, which demonstrated the greatest interaction energy and stable orientation inside the binding pocket. In vitro cytotoxic studies on MCF-7 and MDA-MB-231 breast cancer cell lines demonstrated that compound 4 had the highest antiproliferative activity (IC₅₀ = 5.80 and 6.44 µM, respectively), equivalent to doxorubicin and sorafenib. Compound 3 had significant effects, whereas compounds 9 and 10 showed modest efficacy. Notably, compound 4 exhibited little toxicity to WI-38 normal fibroblasts (IC₅₀ = 51.61 µM), suggesting selectivity for cancer cells. Flow cytometric analyses demonstrated that compound 4 produced G₀/G₁ cell-cycle arrest (82.77%) and initiated apoptosis (35.19%) with little necrosis, therefore validating its CDK4-dependent mechanism. These results together identify compound 4 as a powerful, selective, and environmentally friendly synthetic CDK4 inhibitor, serving as a viable candidate for the future development of tailored anti-breast cancer therapies.
Santamarine Synergizes With Cisplatin via ROS/JNK Axis to Selectively Induce Apoptosis and DNA Damage in Oral Cancer Cells In Vitro.
Lu HI, Chen KL, Chen CY … +6 more , Yen CY, Farooqi AA, Chien TM, Jeng JH, Chen BH, Chang HW
Drug Dev Res · 2026 Jun · PMID 42187533 · Publisher ↗
Santamarine (SAMA), a Michelia compressa-derived sesquiterpene lactone, exhibits ROS‑mediated anticancer activity; however, its potential mechanisms and synergy with cisplatin in oral cancer have not been explored. This...
Santamarine (SAMA), a Michelia compressa-derived sesquiterpene lactone, exhibits ROS‑mediated anticancer activity; however, its potential mechanisms and synergy with cisplatin in oral cancer have not been explored. This study investigated SAMA and cisplatin's combined effects and underlying ROS/MAPK mechanisms of action on oral cancer cells. The combination significantly reduced viability (ATP assay) in oral cancer Ca9‑22 and CAL 27 cells compared with either agent alone, with synergistic indices confirming enhanced antiproliferation. Moreover, this combination markedly suppressed colony formation and cell migration. SAMA/cisplatin induced subG1 accumulation and G2/M arrest, elevated cellular and mitochondrial ROS, and promoted apoptosis, as evidenced by increased annexin V positivity and caspase‑3, -8, and -9 activation, while DNA damage markers γH2AX and 8‑OHdG were also markedly elevated. In contrast, normal oral S‑G cells showed minimal cytotoxic damage and mechanical changes, suggesting selectivity. Mechanistically, JNK inhibition rescued the antiproliferative response and suppressed apoptosis, caspase activation, and DNA damage. Pretreatment with the ROS scavenger NAC attenuated all test effects, confirming ROS dependence. Together, these findings demonstrate that SAMA synergizes with cisplatin to selectively enhance oxidative stress, apoptosis, and DNA damage in oral cancer cells via ROS‑dependent JNK signaling, highlighting its potential as a cisplatin adjunct.
Nanobodies: Pioneering Next-Generation Tools in Modern Medicine.
Folorunsho OG, Fernandes Q, Ezekiel AO … +1 more , Wilson AB
Drug Dev Res · 2026 Jun · PMID 42170900 · Publisher ↗
Nanobodies, also known as single-domain antibodies or Variable Heavy domain of Heavy chain antibody, are unique antibody fragments derived from camelid heavy-chain antibodies. Due to their small size, stability, and high...
Nanobodies, also known as single-domain antibodies or Variable Heavy domain of Heavy chain antibody, are unique antibody fragments derived from camelid heavy-chain antibodies. Due to their small size, stability, and high specificity, nanobodies have gained significant attention for therapeutic and diagnostic applications across various diseases, including cancer, infectious diseases, and neurodegenerative disorders. Their structural simplicity allows efficient production in microbial systems, offering a scalable and cost-effective alternative to traditional monoclonal antibodies. In cancer, nanobodies are effective for targeted drug delivery, improved tumor imaging, and enhanced penetration into solid tumors. Moreover, the versatility of engineered nanobodies extends to the treatment of neurodegenerative diseases, where they may possess the ability to cross the blood-brain barrier, allowing for targeted delivery within the central nervous system. Additionally, nanobodies demonstrate promise in neutralizing toxins, inhibiting inflammatory responses, and modulating the immune system, showcasing their adaptability in treating infectious and inflammatory diseases. Despite their advantages, challenges such as limited half-life, potential immunogenicity, and regulatory hurdles remain. This review explores the structural and functional characteristics of nanobodies, their applications in various disease therapies, and current strategies to overcome these therapeutic limitations.
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