An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors

• Published in: Chemical biology & drug design 2018-12, Vol.92 (6), p.1933-1939
• Main Authors: Khadkikar, Pratima, Goud, N. Sridhar, Mohammed, Arifuddin, Ramamoorthy, Gayathri, Ananthathatmula, Ragamanvitha, Doble, Mukesh, Rizvi, Arshad, Banerjee, Sharmista, Ravi, Alvala, Alvala, Mallika
• Format: Article
• Language: English
• Subjects: Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Bacillus subtilis - drug effects; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Binding Sites; bisindole methanes; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - metabolism; docking; FtsZ; Green Chemistry Technology; GTPase activity; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Methane - chemistry; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium smegmatis - drug effects; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Protein Structure, Tertiary
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13363

The rising multidrug‐resistant Mycobacterium tuberculosis (Mtb) strain made current anti‐TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity. In the present study, we demonstrated for the first time bisindole derivatives as potential MtbFtsZ inhibitors. The synthesis of bisindole derivatives has been carried out using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Among the synthesized bisindole derivative, I16 and I5 showed 62.29% and 56.86% inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by two folds. Further compound I16 inhibited Mtb growth with a MIC of 37.5 μg/ml. To explain these interactions, detailed Molecular docking studies have been carried out and found to be supportive to the biological activity. In this study, 21 bisindole derivatives were synthesized using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Two compounds I5 and I16 showed inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by twofolds upon in‐vitro evaluation. Further compound I16 inhibited Mtb growth with an MIC of 37.5 μg/ml. The experimental data were supported by molecular docking studies.