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This report explores the potential of novel 6-aryloxy-2-aminopyrimidine-benzonitrile scaffolds as promising anti-infective agents in the face of the increasing threat of infectious diseases. Starting from 2-amino-4,6-dichloropyrimidine, a series of 24 compounds inspired from the antiviral drugs dapivirine, etravirine, and rilpivirine were designed and synthesized via a two-step reaction sequence in good yields. Biological testing of synthetic analogs revealed potent inhibition against both viral and tuberculosis targets. Notably, compounds 5p (2,4-dimethyl substitution; IC 50  = 44 ± 4.9 µM; selectivity index [SI] = 20) and 5 s (3-thiophenphenyl; IC 50  = 6 ± 1 µM; SI = 120) showed significant antiviral activity against pandemic influenza virus A/Puerto Rico/8/34 (H1N1) with positive toxicity profiles and also exhibited good IC 50 values (5p, IC 50  = 10 ± 2 µM; SI = 9 and 5 s, IC 50  = 16 ± 2 µM; SI = 60) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Wuhan strain) compared with favipiravir. In addition, analogs 5a, 5r, 5t, and 5u showed good antitubercular activity against Mycobacterium tuberculosis H37Rv strain and compounds 3, 5f, 5n, and 5q showed moderate antibacterial activity against gram+ve and gram-ve bacterial strains, suggesting that this scaffold has a broad spectrum of therapeutic effects., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Substituted saturated N-heterocycles have gained momentum as effective scaffolds for the development of new drugs. In this study, we coupled partly saturated benzothiazoles with substituted piperazines and evaluated their antimicrobial activity. Following a three-step reaction sequence from commercially available cyclic 1,3-diones, a series of novel 2-[4-substituted-1-piperazinyl]-N-(7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acetamides (7a-af) were synthesised. 2-Amino-5,6-dihydro-benzo[d]thiazol-7(4H)-ones, obtained through the condensation of cyclohexane-1,3-diones with thiourea, were acetylated with chloroacetic chloride and then reacted with N-substituted piperazines 6a-p to give the desired products 7a-af in excellent yields. All 32 new compounds were fully characterised by their 1 H-nuclear magnetic resonance (NMR), 13 C-NMR and high-resolution mass spectrometry spectra. The synthetic compounds 7a-af were tested in vitro for their efficacy as antimicrobials against pathogenic strains of Gram-positive and Gram-negative bacteria, Streptococcus mutans and Salmonella typhi, respectively, as well as against fungal strains, including Candida albicans 3018 and C. albicans 4748. Ciprofloxacin and fluconazole served as the reference drugs. While compounds 7c and 7l showed inhibition against fungal strains with zones of inhibition of 11 and 1 mm, respectively, four analogues (7d, 7l, 7n, and 7r) demonstrated strong antibacterial action (zone of inhibition in the range of 10-15 mm). Three compounds (7j, 7l, and 7w) also exhibited moderate antitubercular activity (MIC: 6.25 µg/mL) against Mycobacterium tuberculosis H37Rv. Molecular docking investigations and the predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the potent compounds made this scaffold useful as a pharmacologically active framework for the development of potential antimicrobial hits., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Influenza remains a highly pathogenic and hardly controlled human infection. The ability of selecting drug-resistant variants necessitates the search and development of novel anti-influenza drugs. Herein, we describe the synthesis and evaluation of a series of novel 2-substituted 7,8-dihydro-6H-imidazo[2,1-b][1,3]benzothiazol-5-ones 3a-k for their virus-inhibiting activity against influenza A virus. The new analogues 3a-k prepared in two steps from commercially available cyclohexane-1,3-diones were fully characterized by their NMR and mass spectral data. Among the new derivatives screened for cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells, three analogues 3i-k containing a thiophene unit were found to exhibit high virus-inhibiting activity (high SI values) and a favorable toxicity profile. The compound 3j (CC 50 : >1000 μM, SI = 77) with higher potency is the best anti-influenza hit analogue for further structural optimization and drug development. The most active compounds did not inhibit viral neuraminidase and possess therefore other targets and mechanisms of activity than the currently used neuraminidase inhibitors., (© 2018 Deutsche Pharmazeutische Gesellschaft.)