Infectious diseases are the significant global health problem because of drug resistance to most classes of antimicrobials. Interest is growing in the development of new antimicrobials in pharmaceutical discovery. For that reason, the urgency for scientists to find and/or develop new important molecules is needed. Many natural active molecules that exhibit various biological activities have been isolated from the nature. For the present research, a new selected set of aminobenzoquinones, denoted as plastoquinone analogs (PQ1-24), was employed for their in vitro antimicrobial potential in a panel of seven bacterial strains (three Gram-positive and four Gram-negative bacteria) and three fungi. The results revealed PQ analogs with specific activity against bacteria including Staphylococcus epidermidis and pathogenic fungi, including Candida albicans. PQ8 containing methoxy group at the ortho position on the phenylamino moiety exhibited the highest growth inhibition against S. epidermidis with a minimum inhibitory concentration of 9.76 μg/mL. The antifungal profile of all PQ analogs indicated that five analogs (while PQ1, PQ8, PQ9, PQ11, and PQ18 were effective against Candida albicans, PQ1 and PQ18 were effective against Candida tropicalis) have potent antifungal activity. Selected analogs, PQ1 and PQ18, were studied for biofilm evaluation and time-kill kinetic study for better understanding.

Chemistry Department Engineering Faculty Istanbul University Cerrahpasa Avcilar 34320 Istanbul Turkey

Chemistry Department Gebze Technical University Gebze 41400 Kocaeli Turkey

Department of Chemistry Faculty of Science Istanbul University Vezneciler 34134 Istanbul Turkey

Pharmaceutical Microbiology Department Pharmacy Faculty Istanbul University Beyazit 34116 Istanbul Turkey

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Bayrak N et al (2017) Synthesis, computational study, and evaluation of in vitro antimicrobial, antibiofilm, and anticancer activities of new sulfanyl aminonaphthoquinone derivatives. Lett Drug Des Discov 14:647–661 DOI

Bayrak N, Yıldırım H, Yıldız M, Radwan MO, Otsuka M, Fujita M, Ciftci HI, Tuyun AF (2020) A novel series of chlorinated plastoquinone analogs: design, synthesis, and evaluation of anticancer activity. Chem Biol Drug Des 95(3):343–354 DOI

Belorgey D, Lanfranchi DA, Davioud-Charvet E (2013) 1,4-naphthoquinones and other NADPH-dependent glutathione reductase-catalyzed redox cyclers as antimalarial agents. Curr Pharm Design 19:2512–2528 DOI

Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48:1–12 DOI

Brandy Y et al (2012) Synthesis and cytotoxic activities of some 2-Arylnaphtho[2,3-d]oxazole-4,9-dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines. Investig New Drugs 30:1709–1714 DOI

Butler MS (2008) Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 25:475–516 DOI

Campanini-Salinas J et al. (2018) A new kind of quinonic-antibiotic useful against multidrug-resistant S-aureus and E-faecium infections. Molecules 23 Artn 1776

Cerone M, Uliassi E, Prati F, Ebiloma GU, Lemgruber L, Bergamini C, Watson DG, de A M Ferreira T, Roth Cardoso GSH, Soares Romeiro LA, de Koning HP, Bolognesi ML (2019) Discovery of sustainable drugs for neglected tropical diseases: cashew nut shell liquid (CNSL)-based hybrids target mitochondrial function and ATP production in Trypanosoma brucei. ChemMedChem 14:621–635 DOI

Ciftci HI et al (2019) Discovery and structure-activity relationship of plastoquinone analogs as anticancer agents against chronic myelogenous leukemia cells. Arch Pharm 352(12):1900170 DOI

Clinical and Laboratory Standards Institute (CLSI), Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved Standard–Second Edition (1997). Wayne, PA, USA

Clinical and Laboratory Standards Institute (CLSI), Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically (2006). Wayne, PA, USA

de Oliveira JFA, Saito A, Bido AT, Kobarg J, Stassen HK, Cardoso MB (2017) Defeating bacterial resistance and preventing mammalian cells toxicity through rational design of antibiotic-functionalized nanoparticles. Sci Rep 7:1326 DOI

Dey D, Ray R, Hazra B (2014) Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates. Phytother Res 28:1014–1021 DOI

Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193 DOI

Döşler S, Mataraci E, Başpinar-Küçük H, Yusufoǧlu A (2015) Antibacterial and anti-biofilm activities of new chiral and racemic 1,3-Dioxolanes. Journal of Pharmacy of Istanbul University 45:19–28

Durand GA, Raoult D, Dubourg G (2019) Antibiotic discovery: history, methods and perspectives. Int J Antimicrob Ag 53:371–382 DOI

Duval RE, Grare M, Demore B (2019) Fight against antimicrobial resistance: we always need new antibacterials but for right bacteria. Molecules 24(17):3152

Egleton JE, Thinnes CC, Seden PT, Laurieri N, Lee SP, Hadavizadeh KS, Measures AR, Jones AM, Thompson S, Varney A, Wynne GM, Ryan A, Sim E, Russell AJ (2014) Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1. Bioorg Med Chem 22:3030–3054 DOI

Gibbons S (2004) Anti-staphylococcal plant natural products. Nat Prod Rep 21:263–277 DOI

Glamoclija U et al. (2018) Synthesis, biological evaluation and docking studies of benzoxazoles derived from thymoquinone. Molecules 23

Halicki PCB et al (2018) Naphthoquinone derivatives as scaffold to develop new drugs for tuberculosis treatment. Front Microbiol 9

Heinrich M, Barnes J, Prieto-Garcia J, Gibbons S, Williamson E (2018) Fundamentals of pharmacognosy and phytotherapy. 3rd edn. Elsevier

Jamil B, Habib H, Abbasi SA, Ihsan A, Nasir H, Imran M (2016) Development of cefotaxime impregnated chitosan as nano-antibiotics: De novo strategy to combat biofilm forming multi-drug resistant pathogens. Front Microbiol 7 doi: Artn 330

Janeczko M, Demchuk OM, Strzelecka D, Kubinski K, Maslyk M (2016) New family of antimicrobial agents derived from 1,4-naphthoquinone. Eur J Med Chem 124:1019–1025 DOI

Janeczko M, Kubiński K, Martyna A, Muzyczka A, Boguszewska-Czubara A, Czernik S, Tokarska-Rodak M, Chwedczuk M, Demchuk OM, Golczyk H, Masłyk M (2018) 1,4-Naphthoquinone derivatives potently suppress Candida albicans growth, inhibit formation of hyphae and show no toxicity toward zebrafish embryos. J Med Microbiol 67:598–609 DOI

Jordao AK, Novais J, Leal B, Escobar AC, dos Santos HM, Castro HC, Ferreira VF (2013) Synthesis using microwave irradiation and antibacterial evaluation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-naphthoquinones. Eur J Med Chem 63:196–201 DOI

Kawamukai M (2018) Biosynthesis and applications of prenylquinones. Biosci Biotechnol Biochem 82:963–977 DOI

Klepser ME, Ernst EJ, Lewis RE, Ernst ME, Pfaller MA (1998) Influence of test conditions on antifungal time-kill curve results: proposal for standardized methods. Antimicrob Agents Chemother 42:1207–1212 DOI

Klepser ME et al (2001) Multi-center evaluation of antifungal time-kill methods. J Infect Dis Pharmacother 5:29–41 DOI

Masadeh MM, Mhaidat NM, Alzoubi KH, Hussein EI, Al-Trad EI (2013) In vitro determination of the antibiotic susceptibility of biofilm-forming Pseudomonas aeruginosa and Staphylococcus aureus: possible role of proteolytic activity and membrane lipopolysaccharide. Infect Drug Resist 6:27–32 DOI

Mataraci E, Dosler S (2012) In vitro activities of antibiotics and antimicrobial cationic peptides alone and in combination against methicillin-resistant Staphylococcus aureus biofilms. Antimicrob Agents Ch 56:6366–6371 DOI

Moreira CS, Silva ACJA, Novais JS, Sa Figueiredo AM, Ferreira VF, da Rocha DR, Castro HC (2017) Searching for a potential antibacterial lead structure against bacterial biofilms among new naphthoquinone compounds. J Appl Microbiol 122:651–662 DOI

National Committee for Clinical Laboratory Standards (NCCLS). Methods for determining bactericidal activity of antimicrobial agents (1999). Wayne, NCCLS

Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:461–477 DOI

Novais JS et al (2018) Antibacterial naphthoquinone derivatives targeting resistant strain Gram-negative bacteria in biofilms. Microb Pathog 118:105–114 DOI

Otto M (2009) Staphylococcus epidermidis-the ‘accidental’ pathogen. Nat Rev Microbiol 7:555–567 DOI

Pentz-Murr A, Piddock LJV (2019) Together towards a common goal: REVIVE, a community of antimicrobial researchers brought together by the Global Antibiotic Research & Development Partnership (GARDP). J Antimicrob Chemother 74:1769–1770 DOI

Pingaew R, Prachayasittikul V, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V (2015) Novel 1,4-naphthoquinone-based sulfonamides: synthesis, QSAR, anticancer and antimalarial studies. Eur J Med Chem 103:446–459 DOI

Prachayasittikul V, Pingaew R, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V (2014) Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives. Eur J Med Chem 84:247–263 DOI

Rabin N, Zheng Y, Opoku-Temeng C, Du YX, Bonsu E, Sintim HO (2015) Agents that inhibit bacterial biofilm formation. Future Med Chem 7:647–671 DOI

Ravichandiran P, Masłyk M, Sheet S, Janeczko M, Premnath D, Kim AR, Park BH, Han MK, Yoo DJ (2019a) Synthesis and antimicrobial evaluation of 1,4-naphthoquinone derivatives as potential antibacterial agents. ChemistryOpen 8:589–600 DOI

Ravichandiran P, Subramaniyan SA, Kim SY, Kim JS, Park BH, Shim KS, Yoo DJ (2019b) Synthesis and anticancer evaluation of 1,4-naphthoquinone derivatives containing a phenylaminosulfanyl moiety. ChemMedChem 14:532–544 DOI

Ryu CK, Oh SY, Choi SJ, Kang DY (2014) Synthesis of antifungal evaluation of 2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-diones. Chem Pharm Bull 62:1119–1124 DOI

Sendl A, Chen JL, Jolad SD, Stoddart C, Rozhon E, Kernan M, Nanakorn W, Balick M (1996) Two new naphthoquinones with antiviral activity from Rhinacanthus nasutus. J Nat Prod 59:808–811 DOI

Tuyun AF, Yıldız M, Bayrak N, Yıldırım H, Mataracı Kara E, Jannuzzi AT, Celik BO (2019) Discovery of a new family of heterocyclic amine linked plastoquinone analogs for antimicrobial evaluation. Drug Dev Res 80:1098–1109 DOI

Wellington KW, Kolesnikova NI, Hlatshwayo V, Saha ST, Kaur M, Motadi LR (2019a) Anticancer activity, apoptosis and a structure-activity analysis of a series of 1,4-naphthoquinone-2,3-bis-sulfides Investig New Drugs, in press ( https://doi.org/10.1007/s10637-019-00775-7 ), 1, 13

Wellington KW, Kolesnikova NI, Nyoka NBP, McGaw LJ (2019b) Investigation of the antimicrobial and anticancer activity of aminonaphthoquinones. Drug Dev Res 80:138–146 DOI

Wellington KW, Nyoka NBP, McGaw LJ (2019c) Investigation of the antibacterial and antifungal activity of thiolated naphthoquinones. Drug Dev Res 80:386–394 DOI

WHO (2018) The top 10 causes of death

Xu K, Xiao ZY, Tang YB, Huang L, Chen CH, Ohkoshi E, Lee KH (2012) Design and synthesis of naphthoquinone derivatives as antiproliferative agents and 20S proteasome inhibitors. Bioorg Med Chem Lett 22:2772–2774 DOI

Yildirim H, Bayrak N, Tuyun AF, Kara EM, Celik BO, Gupta GK (2017) 2,3-disubstituted-1,4-naphthoquinones containing an arylamine with trifluoromethyl group: synthesis, biological evaluation, and computational study. RSC Adv 7:25753–25764 DOI