Ratrey, PoonamPoonamRatreyDas Mahapatra, AmarjyotiAmarjyotiDas MahapatraPandit, ShinyShinyPanditHadianawala, MurtuzaMurtuzaHadianawalaMajhi, SasmitaSasmitaMajhiMishra, AbhijitAbhijitMishraDatta, BhaskarBhaskarDatta2025-08-312025-08-312021-08-1310.1039/d1ra03882f2-s2.0-85115162748https://d8.irins.org/handle/IITG2025/25340Hybrid antimicrobials that combine the effect of two or more agents represent a promising antibacterial therapeutic strategy. In this work, we have synthesizedN-(4-(4-(methylsulfonyl)phenyl)-5-phenylthiazol-2-yl)benzenesulfonamide derivatives that combine thiazole and sulfonamide, groups with known antibacterial activity. These molecules are investigated for their antibacterial activity, in isolation and in complex with the cell-penetrating peptide octaarginine. Several of the synthesized compounds display potent antibacterial activity against both Gram-negative and Gram-positive bacteria. Compounds with 4-tert-butyl and 4-isopropyl substitutions exhibit attractive antibacterial activity against multiple strains. The isopropyl substituted derivative displays low MIC of 3.9 μg mL⁻¹againstS. aureusandA. xylosoxidans. The comparative antibacterial behaviour of drug-peptide complex, drug alone and peptide alone indicates a distinctive mode of action of the drug-peptide complex, that is not the simple sum total of its constituent components. Specificity of the drug-peptide complex is evident from comparison of antibacterial behaviour with a synthetic intermediate-peptide complex. The octaarginine-drug complex displays faster killing-kinetics towards bacterial cells, creates pores in the bacterial cell membranes and shows negligible haemolytic activity towards human RBCs. Our results demonstrate that mere attachment of a hydrophobic moiety to a cell penetrating peptide does not impart antibacterial activity to the resultant complex. Conversely, the work suggests distinctive modes of antibiotic activity of small molecules when used in conjunction with a cell penetrating peptide.trueArticlehttps://pubs.rsc.org/en/content/articlepdf/2021/ra/d1ra03882f2046206928581-2859213 August 202111arJournal11WOS:000696361100017