Fluorinated phospholipid analogs Edelfosine and Ilmofosine drug reveal expressive potential as antineoplastic factors though targeted interaction with heat shock protein (HSP70KDa1A), an essential mediator in cancer pathophysiology. Using evolved computational approaches, this research evaluated their ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles receptor binding affinities and molecular dynamics. Molecular docking discernible vigorous interactions with Edelfosine drug displaying greater binding stability and consistent hydrogen bonding as confirmed by 100 ns molecular dynamics simulations. Comparative interpretation emphasized Edelfosine drug enhanced pharmacokinetic properties depicted by lower RMSD values, stable solvent-accessible surface area and reduced structural fluctuations relative to Ilmofosine drug. Functional annotation and phylogenetic investigation affirmed the evolutionary conservation and pivotal biological function of heat shock protein (HSP70KDa1A). These findings position Edelfosine drug as a promising candidate for targeted cancer therapy appropriated further experimental validation to elucidate its mechanisms of action and therapeutic efficacy.

Cutaneous leishmaniasis, a neglected tropical disease (NTD) caused by Leishmania tropica, Leishmania major and other members of the same species, poses significant challenges in the public health sector, especially in developing countries. The limitations of current treatments, including toxicity, resistance, availability, and cost effectiveness, necessitate the development of novel therapeutics. This study investigated the leishmanicidal potential of five Thiadiazine thione derivatives (THTT) against L. tropica, at a dose range of 25–426 µM using an MTT assay. Compounds T9, T24, T25 (tris-THTT) and PG (mono-THTT) exhibited notable IC₅₀ values of 20.01, 26.94, 27.71, and 82.79 µM, respectively. Moreover, the same compounds demonstrated promising docking scores against critical leishmanial enzymes, such as Trypanothione reductase, Trypanothione synthetase, Leishmanolysin, and C24-sterol methyl transferase. Hemolytic assay revealed that all the compounds are non-toxic at lower concentrations. Mono-THTTs (PG and BG) showed higher CC₅₀ values i.e., 401.65, 375.68 as compared to tris-THTTs (T9, T24, T25) which is 104.61, 104.51 and 89.73 µM respectively. All derivatives showed high selectivity indices (SI) compared to the standard drug Amphotericin-B. Furthermore, in-silico investigations targeting COX1 and COX2 enzymes unveiled a high affinity of the tested compounds towards these enzymes, indicating their potential involvement as anti-inflammatory agents. Subsequent in-vitro HRBC membrane stabilization and egg albumin denaturation assays confirmed the anti-inflammatory potential of all the compounds. These findings validate THTT derivatives as an effective and novel class of anti-leishmanial agents against L. tropica with a favorable safety profile and potential anti-inflammatory properties. Further research is recommended to elucidate their mechanisms of action and in-vivo efficacy.

Background/Objectives: Thiadiazine thione (THTT) has gained significant interest owing to its pharmacological potentials, particularly its antiparasitic and anti-inflammatory properties. Leishmaniasis is a clinical syndrome caused by infection with Leishmania species and is associated with an inflammatory response and nociception. The available treatments against leishmaniasis are inadequate, as they are associated with high cost, toxicity, and increased resistance. Methods: In the current study, the antileishmanial potential of five Thiadiazine thione derivatives (C1–C5) was evaluated in vivo against Leishmania tropica. Experiments were performed on BALB/c mice infected with promastigotes and treated with THTT derivatives for 15 days. Additionally, the derivatives were evaluated for their anti-inflammatory, antinociceptive, antipyretic, and antisedative properties using standardized models, including carrageenan-induced paw edema, acetic acid-induced abdominal writhes, yeast-induced fever, and white wood apparatus, respectively. Results: Of the tested derivatives, C5 exhibited the most promising results, with a 61.78% reduction in lesion size and significant decrease in parasite load. Among the derivatives, C1 showed the highest anti-inflammatory activity, with 63.66% inhibition in the paw edema test at the 5th hour post treatment. In the antipyretic assay, C1 and C5 were able to reduce body temperature to a normal level within 1 h of treatment. Furthermore, compounds C4, C2, and C1 showed high nociceptive activity, while C1 and C5 demonstrated the most notable antisedative effects (94 ± 2 and 92 ± 1, respectively), outperforming the standard drug diazepam (13 ± 1). Conclusion: These in vivo findings suggest that THTT derivatives have the potential to serve as a template for developing leishmanicidal drugs, with added anti-inflammatory and analgesic properties.