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The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.

A series of 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12 (or 14,15)-didehydroandrographolide-19-oic acid derivatives were designed, synthesized and screened in vitro against the mouse fibroblast cell lines NIH-3T3. Thirteen compounds 8a-f, 14a-c, 14e-f, and 18a-b were found to exhibit better anti-fibrotic activities than andrographolide, with compounds 8b and 14e displaying best activity with IC50 values of 12.86 and 13.57 μM against NIH-3T3 respectively. Further anti-fibrotic investigation was performed in terms of PCR and western bolt analysis. Our study demonstrated that compounds 8b and 14e suppressed effectively the expression of α-smooth muscle actin, fibronectin and collagen in NIH-3T3. Preliminary structure-activity analysis revealed that 14-deoxygenation and 19-carboxylation of andrographolide could significantly improve its anti-fibrotic effect, which made 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12-didehydroandrographolide-19-oic acid promising leads for the development of new anti-fibrotic agents.