8-Quinoline-oxadiazole ethanone and acetamide hybrids as potential dual HIV-1 entry and mycobacterium tuberculosis inhibitors

• Eighteen (18) 8-quinoline-oxadiazole ethanone ( 12a-j ) and acetamides ( 15a-h ) hybrids have been synthesized and evaluated as anti-HIV and antitubercular agents. • Acetamides 15f and 15g exhibited submicromolar potency against Mtb (MIC 90 = 0.25 µM) and HIV-1 subtype B (IC 50 = 0.281 µM), respectively. • All the compounds exhibited a good cytotoxicity profile with CC 50 greater than 100 µM. • In vitro time-of-addition studies revealed potent inhibition of the viral attachment phase of the viral lifecycle. • In silico docking studies revealed binding interactions with key amino acids in both diseases, while also possessing acceptable ADME properties. Compounds containing the 8-quinoline and oxadiazole pharmacophores exhibit a broad spectrum of biological properties against infectious diseases such as Human immunodeficiency virus (HIV) and tuberculosis (TB). In this study, eighteen (18) 8-quinoline-oxadiazole ethanone ( 12a-j ) and acetamides ( 15a-h ) hybrids have been synthesized and evaluated as anti-HIV and antitubercular agents. Compound 15f (MIC 90 = 0.25 µM) was the most active against the H 37 Rv strain of Mycobacterium tuberculosis (Mtb), showing a 38-fold superior activity than the reference drug ethambutol (MIC 90 = 9.68 µM), while compound 15g exhibited good activity (IC 50 = 0.281 µM) against HIV-1. Furthermore, 15g exhibited an acceptable cytotoxicity profile with CC50 > 100 µM and a selective index (SI) > 7000. The HIV-1 time of addition studies revealed that 15g strongly inhibits the viral entry stage of the HIV life cycle, while also showing weak inhibition of reverse transcription, integration, and proteolysis. Molecular docking studies indicated that compound 15g interacted with key amino residues in the active site of the HIV-1 CCR5 and gp120 protein receptors. In silico drug-likeness parameters/ADME properties showed that the hybrids followed the acceptance criteria. Thus, compound 15g can be a valuable starting material for further optimization in the search for dual active compounds against HIV and Mtb .