A series of twenty six structurally diverse a-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay. Among them, seven compounds (1-7) exhibited anti-leishmanial potency against the L. donovani promastigote with IC 50 values in the low micromolar range. The structure-activity relationships were quantitatively evaluated by a statistically reliable CoMFA model with high predictive abilities (r 2 pred ¼ 0.87, r 2 ncv ¼ 0.985).
Diabetes mellitus is rising globally touching more than 180 million people worldwide. This is prevailing mostly in type 2 diabetes and according to WHO report the incidence is likely to be more than doubled by 2030. α-Glucosidase inhibitors work by reducing the amount of glucose that the intestines absorb from food. In this work, forty-five benzimidazole analogues were studied using 3D QSAR, HQSAR, pharmacophore mapping and based on their results 60 compounds were designed. The results show that the best Comparative Molecular Field Analysis (CoMFA) model has q2 = 0.742 and r2 = 0.973, and the best Comparative Molecular Similarity Indices Analysis (CoMSIA) model has q2 = 0.679 and r2 = 0.918. For HQSAR the best model has q2 = 0.773 and r2 = 0.964. The r2 value for boostrap for CoMFA and CoMSIA are 0.98 and 0.97 respectively. Pharmacophore mapping revealed varied bioactive regions of ligand. Thus, these compounds could be used as lead for designing the synthesis of potent alpha-glucosidase inhibitors.
Keywords: Acarbose, Alpha-glucosidase inhibition, Benzimidazoles, Molecular modelling, Post-prandial hyperglycemia
A series of alkynylgold(I)
phosphine complexes containing methoxy-substituted cinnamide moieties
(3a–3c and 4a–4c) have been synthesized and characterized. All of the synthesized
complexes were evaluated for their cytotoxicity against three human
cancer cell lines A549 (lung), D24 (melanoma), and HT1080 (fibrosarcoma)
and the human embryonic kidney 293 cell line (Hek293T) as a proxy
model for noncancer cells. Most of the synthesized compounds showed
antiproliferative activity against cancer cell lines at low micromolar
concentrations. Among these, complex 3c showed a broad
spectrum of anticancer activity with IC50 values in the
range of 1.53–6.05 μM against all tested cancer lines.
Complex 3c possessed 20 times higher cytotoxicity than
the reference drug cisplatin against D24 melanoma cells and showed
significant anticancer activity in 3D spheroidal models of melanoma
cells. Mechanistic investigations of 3c activity indicate
thioredoxin reductase inhibition through steric and hydrogen-bonding
interactions, followed by the induction of oxidative stress and a
mitochondrial pathway of cell death. Compound 3c also
showed significant antiangiogenic properties in a transgenic zebrafish
Tg(fli1a:EGFP) in vivo model.
This article describes studies on the design, synthesis, and biological evaluation of pyrazole‐containing β‐amino carbonyl compounds (5a–5q) as DPP‐4 inhibitors and anti‐diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3)3) catalyst in the presence of ethanol and produced pyrazole‐containing β‐amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP‐4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme‐based in vitro DPP‐4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP‐4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5 nM, respectively. The most potent compound, 5j, was further selected for in vivo anti‐diabetic activity using an STZ‐induced diabetic mice model, and 5j showed a significant diabetic control effect.
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