Drug design, development and therapy · 2026
Synthesis and Biological Evaluation of Imidazopyridine-Isatin Hybrids as Inhibitors of Leishmania major Growth.
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El Hassab Mahmoud A, Eldehna Wagdy M, Elsayed Zainab M, Elbadawi Mostafa M, Negmeldin Ahmed T, Balaha Marwa, Nasralla Sherry N, Monir Rehan, Ibrahim Tamer M, Abe Manabu, Tawfik Haytham O, Bekhit Adnan A, Hemeda Loah R
Аннотация
INTRODUCTION: More than 20 different species of Leishmania cause leishmaniasis, a multifaceted disease that ranges from mild cutaneous lesions to fatal visceral forms.
METHODS: Sixteen novel hybrids were designed by covalently linking an imidazo[1,2-a]pyridine core to an isatin scaffold via a hydrazide linker, and their in vitro anti-promastigote, anti-amastigote, cytotoxicity, and molecular docking profiles were evaluated, with folate-rescue assays used to assess the anti-folate mechanism.
RESULTS: Several compounds showed potent anti-leishmanial activity compared to miltefosine, with the lead compound 5b exhibiting strong anti-promastigote (IC5 0 = 0.84 ± 0.06 μM) and anti-amastigote (IC5 0 = 1.28 ± 0.18 μM) activities, significantly surpassing miltefosine. Folic and folinic acids reversed the activity of 5b, confirming an anti-folate mechanism similar to that of the Lm-PTR1 inhibitor trimethoprim. The most active compounds showed higher selectivity indices (SI = 12.74) than miltefosine (SI = 438.03), and docking against Lm-PTR1 provided a plausible explanation for their potency, while in silico predictions indicated favorable drug-likeness and pharmacokinetic properties.
CONCLUSION: These findings highlight a promising new chemotype targeting the leishmanial folate pathway and expand the chemical diversity available for anti-leishmanial drug development.
METHODS: Sixteen novel hybrids were designed by covalently linking an imidazo[1,2-a]pyridine core to an isatin scaffold via a hydrazide linker, and their in vitro anti-promastigote, anti-amastigote, cytotoxicity, and molecular docking profiles were evaluated, with folate-rescue assays used to assess the anti-folate mechanism.
RESULTS: Several compounds showed potent anti-leishmanial activity compared to miltefosine, with the lead compound 5b exhibiting strong anti-promastigote (IC5 0 = 0.84 ± 0.06 μM) and anti-amastigote (IC5 0 = 1.28 ± 0.18 μM) activities, significantly surpassing miltefosine. Folic and folinic acids reversed the activity of 5b, confirming an anti-folate mechanism similar to that of the Lm-PTR1 inhibitor trimethoprim. The most active compounds showed higher selectivity indices (SI = 12.74) than miltefosine (SI = 438.03), and docking against Lm-PTR1 provided a plausible explanation for their potency, while in silico predictions indicated favorable drug-likeness and pharmacokinetic properties.
CONCLUSION: These findings highlight a promising new chemotype targeting the leishmanial folate pathway and expand the chemical diversity available for anti-leishmanial drug development.