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.
Ureidopenicillins are a class of penicillins which are antibiotics active against gram‐negative bacteria. Herein, we report the synthesis of 2‐aminothiophene‐tethered ureidopenicillin analogues and their in vitro antibacterial and antitubercular activity. Intriguingly, unlike the reported ureidopenicillins which are active against gram‐negative bacteria, the synthesised 2‐aminothiophene‐tethered ureidopenicillins were significantly active against Gram‐positive bacterial strains and showed moderate inhibition towards gram‐negative bacterial strains. Among all the analogs, compound 1 b containing 2‐aminothiophene moiety with minimum inhibitory concentration (MIC): 0.29, 0.32, > 10, > 10 μg/ml for Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa, respectively, showed better anti‐bacterial profile as compared to cephalexin and equipotent to ampicillin and amoxicillin on gram‐positive bacterial strains. All the derivatives were also screened for anti‐TB activity against mycobacterium tuberculosis H37Ra. Among the series, cycloocta‐thiophene‐tethered cephalexin analog 3 c displayed excellent antitubercular activity with MIC values 0.78 μg/ml. Low cytotoxicity and high selectivity index indicate the efficacy of 3 c against mycobacterial infections. The results from present study offer a novel approach to modify the existing drug class of ureidopenicillins to yield antimicrobials with promising utility.
This note reports the synthesis and
peptide formation of a novel
triple G-C-T nucleobase amino acid (NBA) building block featuring
three recognition faces: DDA (G mimic), DAA (C mimic), and ADA (T
mimic). Readily obtainable in multigram scale in a remarkably easy
one-step reaction, this unique NBA building block offers scope for
wide ranging applications for nucleic acid recognition and nucleic
acid peptide/protein interaction studies.
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