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In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones (PS1\u201314) to identify potent and selective bacterial MetAPs inhibitors. Compound PS9 inhibited prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a and SpMetAP1a with Ki values of 0.31, 6.93 and 0.37 \u00b5M, respectively. Interestingly, PS9 inhibited the human analogue HsMetAP1b with Ki (631.7 \u00b5M) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, PS6 and PS9 had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. PS9 showed no significant cytotoxic effect on human RBCs, HEK293 cells and Galleria mellonella larvae in vivo. PS9 inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested PS9 could be a useful candidate for the development of antibacterial alternatives.<\/jats:p>","DOI":"10.3390\/antibiotics11081126","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T21:05:51Z","timestamp":1661115951000},"page":"1126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Design, Synthesis and Mechanistic Studies of Novel Isatin-Pyrazole Hydrazone Conjugates as Selective and Potent Bacterial MetAP Inhibitors"],"prefix":"10.3390","volume":"11","author":[{"given":"Iram","family":"Irfan","sequence":"first","affiliation":[{"name":"Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1574-4796","authenticated-orcid":false,"given":"Asghar","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-3719","authenticated-orcid":false,"given":"Bharati","family":"Reddi","sequence":"additional","affiliation":[{"name":"Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd. 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Rizwanul","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5286-6605","authenticated-orcid":false,"given":"Shailja","family":"Singh","sequence":"additional","affiliation":[{"name":"Host-Parasite Interaction Biology Laboratory, Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-0747","authenticated-orcid":false,"given":"Anthony","family":"Addlagatta","sequence":"additional","affiliation":[{"name":"Division of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0507-8451","authenticated-orcid":false,"given":"Mohammad","family":"Abid","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1057\/s41599-018-0181-x","article-title":"The evolving response to antibiotic resistance (1945\u20132018)","volume":"4","author":"Podolsky","year":"2018","journal-title":"Palgrave Commun."},{"key":"ref_2","first-page":"277","article-title":"The antibiotic resistance crisis: Part 1: Causes and threats","volume":"40","author":"Ventola","year":"2015","journal-title":"Pharm. 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