Abstract

Bu makale, Mycobacterium tuberculosis H37Rv'ye karşı in vitro antimikobakteriyel aktiviteleri için bazı yeni 2-(benzimidazol-2-yl)-3-(4-(4-substitüepiperazin-1-yl)fenil)propannitril türevlerinin sentezini ve aktivitelerinin değerlendirilmesini içermektedir. Bileşikler arasında M. tuberculosis'e karşı 1.56 μg/mL MIC değeri ile en aktif bileşik 4c olarak bulundu. Ek olarak, 4c, besin açlık modeli testinde 2.1 log azalma sağlayarak birinci basamak ilaçlardan daha güçlü antimikobakteriyel aktivite göstermiştir. Hesaplanan fizikokimyasal değerlere dayanarak, bileşiklerin Lipinski'nin "beşler kuralına" ve TPSA/nROT limitlerine uyduğu tahmin edilmektedir. 4c'nin M. tuberculosis LAT enziminin aktif bölgesindeki oryantasyonunu tahmin etmek için moleküler yerleştirme çalışmaları yapıldı. Bu sonuçlar, M. tuberculosis'in hem aktif hem de latent formlarına karşı potansiyeli nedeniyle 4c'nin ilaç geliştirme için iyi bir aday olabileceğini düşündürmektedir.

Keywords

• benzimidazol
• propannitril
• antimikobakteriyel aktivite
• tuberküloz
• besin açlık modeli
• lisin epsilon aminotransferaz

Project Number

THD-2019-17927

Design, Synthesis and Antimycobacterial Activity of 2-(Benzimidazol-2-yl)-propanenitrile Analogs

Abstract

This paper reports the synthesis and evaluation of some new 2-(benzimidazol-2-yl)-3-(4-(4-substitutedpiperazin-1-yl)phenyl)propanenitrile derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. Among them, 4c was found to be the most active compound with MIC of 1.56 μg/mL against M. tuberculosis. In addition, 4c showed 2.1 log reduction against nutrient starved M. tuberculosis which is more potent than first line drugs. Based on their predicted physicochemical values, the compounds obeyed the Lipinski’s "rule of five," and TPSA/nROT limits. Molecular docking studies were performed to estimate the orientation of 4c at the active site of M. tuberculosis LAT enzyme. These results suggest that 4c may be a good candidate for drug development owing to potential against both active and dormant forms of M. tuberculosis.

Keywords

• benzimidazole
• propanenitrile
• antimycobacterial activity
• tuberculosis
• lysine epsilon aminotransferase.
• nutrient starvation model

Supporting Institution

Hacettepe University

Project Number

THD-2019-17927

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