Design and Synthesis of 2‐Amino‐thiophene‐proline‐conjugates and Their Anti‐tubercular Activity against Mycobacterium Tuberculosis H37Ra

Abstract

The emergence of extensively drug resistant tuberculosis (XDR‐TB) and multi‐drug resistant tuberculosis (MDR‐TB) has necessitated the development of new drugs with short chemotherapy treatment regime and cost effectiveness. To overcome these challenges, we are reporting the synthesis of a series of 2‐amino‐thiophene‐proline‐conjugates which show potent in‐vitro and ex‐vivo anti‐tubercular (anti‐TB) activity against mycobacterium tuberculosis (mtb) H37Ra. The synthesis of these 2‐amino‐thiophene‐proline‐conjugates was carried out via solution phase peptide coupling reactions using methyl‐2‐aminothiophene‐3‐carboxylate 8 as an intermediate obtained by modified gewald reaction. Intermediate 8 was coupled with different amino acids to obtain dipeptides 3, 4, 5, 6 a and 7. Priliminary anti‐TB assay data encoureaged us to synthesize modified proline derivatives 6 b‐6 k via formation of a benzoxazinone intermediate 16. Most of these conjugates are active against mtb H37Ra in both active (A) and dormant (D) strains. They are also active against drug resistant mtb H37Ra strains. A trifluoroethyl ester analog, 6 i was the most potent among the series [MIC 1 μg/mL] along with 6 f and 6 g [MIC 2–6 μg/mL]. Cytotoxicity studies suggested that, these compounds are less cytotoxic to human cell lines HeLa, MCF‐7, HUVEC and hence possess high selectivity index (SI). Docking studies revealed that the binding mode of most active compounds 6 i, 6 g and 6 f is in accordance with their bioactivity studies having docking score −8.969, −8.446 and −7.865, respectively. Moreover, in silico ADME properties suggest that all the compounds possess drug like properties.

Tuberculosis: An Overview of the Immunogenic Response, Disease Progression, and Medicinal Chemistry Efforts in the Last Decade toward the Development of Potential Drugs for Extensively Drug-Resistant Tuberculosis Strains

“…With the aim of developing new chemo types, in 2019, Baravkar et. al investigated a series of dipeptides (Figure ), in which different amino acids were tethered to the 2-aminothiophene ring . Derivatives containing the proline (Pro) residue were the most promising and were reported as a new class of tuberculosis inhibitors with potent in vitro and ex-vivo anti-TB activity against both active and dormant Mtb H37Ra (Table ).…”

“…al investigated a series of dipeptides (Figure 19), in which different amino acids were tethered to the 2-aminothiophene ring. 246 Derivatives containing the proline (Pro) residue were the most promising and were reported as a new class of tuberculosis inhibitors with potent in vitro and ex-vivo anti-TB activity against both active and dormant Mtb H37Ra (Table 10). A clear SAR study showed that the change in the chirality of Pro ring does not affect the activity.…”

Synthesis, Optical Properties, Preliminary Antimycobacterial Evaluation and Docking Studies of Trifluoroacetylated 3‐Pyrrolyl Boron‐Dipyrromethene

“…Multi‐drug resistance (MDR) and extensive‐drug resistance (XDR) are growing problems and are fueling the tuberculosis epidemics [36,37] . According to this the development of new compounds being active against M. tuberculosis is relevant [38–45] . A drug screening with M. tuberculosis is hampered with slow growth rate and special working conditions required for making the experiment safe.…”

“…[36,37] According to this the development of new compounds being active against M. tuberculosis is relevant. [38][39][40][41][42][43][44][45] A drug screening with M. tuberculosis is hampered with slow growth rate and special working conditions required for making the experiment safe. Thus, the use of non-pathogenic and fast-growing mycobacterium as a model organism is a good starting point for possible drug search.…”

Synthesis and analgesic activity evaluation of derivatives of 2-[(1,4-dioxo-1-amino-4-arylbutyl-2-en-2-yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid

“…The Gewald aminothiophene fragment is a promising pharmacophore group, since it was found in both natural and synthetic physiologically active compounds [1][2][3][4][5][6]. The synthesis of substituted Gewald aminothiophenes can be carried out using the Gewald reaction [7][8][9].…”