Ahmed Sabt

Fourteen hybrid molecules (3a–g, 5a–g) combining a pyridine core with thiosemicarbazone or thiazolidinone moieties were designed, synthesized, and evaluated in vitro against Leishmania major.

The increase in global life expectancy has resulted in a significant rise in the occurrence of Alzheimer's disease (AD), making it a critical public health burden. Therefore, there is an urgent need to create effective methods to prevent or slow down the progression of the disease. In this regard, fifteen previously reported hybrid molecules ( 7a–c , 10a–j , and 13a,b ), combining 4‐hydroxycoumarin and pyrazolyl indolin‐2‐one structures, were resynthesized and tested for their antioxidant and anti‐Alzheimer properties. Several of these compounds showed moderate to strong biological activity. Among these, compound 7a demonstrated excellent antioxidant capacity (TAC = 80.65 mg gallic acid/g; IRP = 68.90 µg/mL) and impressive free radical scavenging abilities (DPPH = 5.33 µg/mL; ABTS = 4.59 µg/mL; NO = 6.76 µg/mL), comparable to the standard antioxidant ascorbic acid. Additionally, compound 7a demonstrated the robust inhibition of acetylcholinesterase (AChE) with an IC ₅₀ of 6.89 µg/mL, as well as potent inhibition of butyrylcholinesterase (BChE) (IC ₅₀ = 5.93 µg/mL). Molecular docking analyses of compound 7a revealed favorable binding interactions and stable conformations within the enzyme's active site, supporting its strong inhibitory effect. Overall, these findings indicate that this group of hybrid molecules offers a promising framework for developing new cholinesterase‐targeting treatments for AD.

The development of innovative treatment medicines that can overcome drug resistance and intracellular persistence is necessary since tuberculosis (TB) continues to be a significant worldwide health burden.

Toxoplasmosis: a globally prevalent parasitic disease posing a major risk to immunocompromised individuals.

Toxoplasmosis continues to pose significant challenges to public health and animal husbandry, thereby generating an ongoing need for the development of novel therapies through innovative approaches. In response to the persistent pursuit of an optimal chemotherapeutic agent, the present study designed and synthesized new small molecules (6 and 9a-d) featuring an imidazopyridine scaffold linked to isatin derivatives via a hydrazide moiety. The efficacy of these compounds was evaluated against Toxoplasma gondii (ME49 strain) in both in vitro and in vivo murine models of chronic infection. Notably, most of the tested compounds exhibited significant antiparasitic activity. Compound 9a showed the lowest calculated LD₅₀ value, indicating strong potency, while compound 9c demonstrated excellent cysticidal activity in vitro, achieving 100% cyst mortality at concentrations ≥100 µg mL^-1. In vivo, compound 9c was the most effective treatment, reducing brain cyst burden by 82.7%. Molecular analyses indicated that compound 9c significantly reduced T. gondii DNA levels and strongly downregulated pro-inflammatory cytokines. Molecular docking analyses further validated the effective interactions between the synthesized compounds and the target enzyme T. gondii calcium-dependent protein kinase-1 (TgCDPK1). Collectively, these results highlight the promising anti-Toxoplasma potential of imidazopyridine-isatin hybrids, which provides a foundation for the further development of these hybrid molecules as therapeutic agents against toxoplasmosis.

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 ₅₀ values of 0.40 and 0.52 µg/mL, respectively, better than the reference drug pyrimethamine (IC ₅₀ = 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 ₅₀ 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.

The updated guidelines from the World Health Organization highlight that treatment options for multidrug-resistant tuberculosis (MDR-TB) remain limited due to the scarcity of effective drugs. As a result, there is an urgent necessity to develop novel or repurposed drugs that demonstrate efficacy against multidrug-resistant (MDR) strains. In this study, a new series of thiazole-pyridine hybrids were thoughtfully designed and synthesized to assess their potential as antitubercular agents. These compounds were specifically created to target enoyl acyl carrier protein reductase (InhA), a crucial enzyme in the pathogenesis of Mycobacterium tuberculosis. The majority of the compounds evaluated demonstrated substantial antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 3.9 μg mL⁻¹ against Mycobacterium tuberculosis H37Rv. Among them, compound 5a was the most effective, with an MIC of 0.5 μg mL⁻¹. Further evaluations of compound 5a demonstrated its ability to disrupt bacterial biofilms and its strong inhibition of InhA, with an IC₅₀ of 0.19 ± 0.008 μg ml⁻¹, demonstrating superior efficacy compared to triclosan, which was employed as the reference drug. Molecular docking and dynamics analyses demonstrated that the pyridine ring and thiazole group are essential for binding affinity, and the pyridine-thiazole framework in compound 5a formed stable interactions within the active site of InhA.

Introduction: Tuberculosis is a very complicated disease because of how the TB bacteria behaves in the human body. This makes it hard to diagnose, treat, and control. Because of this, the World Health Organization’s latest reports show that there are still very few good treatment options for drug-resistant TB. Methods: A novel series of pyridine-derived compounds were rationally designed and synthesized to evaluate their potential as antitubercular agents. These derivatives were specifically developed to target the enoyl acyl carrier protein reductase (InhA), and molecular docking studies were performed to predict binding modes with InhA. Results: All compounds exhibited notable antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 2.0 μg mL^{− 1} against Mycobacterium tuberculosis H37Rv. Discussion: Derivative 6 was the most potent compound (MIC: 0.5 μg mL^{− 1}), inhibiting intracellular bacteria, disrupting biofilms, and potently targeting InhA (IC₅₀: 0.36 μM). Its pyridine-thiazole scaffold was key for stable binding, as shown by molecular modeling.

Neglected tropical diseases (NTDs) encompass a broad spectrum of infectious diseases predominantly found in tropical and subtropical regions. The limitations of current therapies underscore the critical demand for novel antileishmanial agents. In this investigation, we designed, synthesized, and evaluated ten hybrid compounds (5, 8a–e, and 12a–d) integrating a 7-chloroquinoline scaffold with thiadiazole and thiazole moieties, assessing their in vitro efficacy against Leishmania major. These hybrids exhibited potent activity against the promastigote stage, displaying IC₅₀ values between 0.52 and 3.97 μM, outperforming miltefosine (IC₅₀ = 7.83 μM). Additionally, they demonstrated strong inhibition of the intracellular amastigote form, with IC₅₀ values ranging from 0.76 to 5.62 μM, compared to miltefosine's 8.07 μM. Notably, compound 5 emerged as a highly effective antileishmanial agent against both parasitic stages, while maintaining a favorable safety profile. Mechanistic studies revealed that compound 5 acts via an antifolate mechanism, selectively inhibiting key enzymes in the folate pathway: pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and 100 ns molecular dynamics (MD) simulations demonstrated that the quinoline core occupies a hydrophobic pocket formed by residues Phe113, Leu188, Leu226, and Leu229, engaging in stable hydrophobic interactions and π–π stacking with Phe113. Furthermore, the quinoline scaffold and hydrazinecarbodithioate moiety formed hydrogen bonds with Tyr194, Gly225, and His241, reinforcing binding stability. Our findings introduce a promising new class of antileishmanial agents that disrupt the folate biosynthesis pathway, offering significant therapeutic potential for combating leishmaniasis.