Recent Advances in Anti-Infective Drug DiscoveryRecent Advances in Anti-Infective Drug DiscoveryRecent Advances in Anti-Infective Drug Discovery2772-43442772-4344Bentham Science64455310.2174/0127724344269458231124123935MedicineResearch ArticleGreen Chemistry and In silico Techniques for Synthesis of Novel Pyranopyrazole and Pyrazolo-pyrano-pyrimidine Derivatives as Promising Antifungal AgentsAsgaonkarKalyaniinfo@benthamscience.netChitreTruptiinfo@benthamscience.netPatilShitalinfo@benthamscience.netShevateKrishnainfo@benthamscience.netSagarAshwiniinfo@benthamscience.netGhateDiptiinfo@benthamscience.netShahParthinfo@benthamscience.netDepartment of Pharmaceutical Chemistry, All India Shri Shivaji Memorial Society’s College of Pharmacy0103202419321623107012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/2772-4344/article/view/644553

Background:Every year Invasive Fungal Infections (IFI) are globally affecting millions of people. Candida albicans and Aspergillus niger have been reported as the most infectious and mortality-inducing fungal strains among all pathogenic fungi.

Aim & Objective:To tackle this problem in the current study Pyranopyrazoles and Pyrazolopyrano- pyrimidine derivatives were developed using molecular hybridization, green chemistry and one-pot multicomponent reaction.

Material and Method:In the present work, New Chemical entities (NCE’s) were developed on the basis of Structure activity relationship. All designed NCE’s were screened for ADMET studies using the QikProp module of Schrodinger software. NCE’s with zero violations were further docked on the crystal structure of 14α demethylase, cytochrome P450 and thymidine synthase (PDB ID: 5V5Z, 7SHI, 1BID). Selected molecules were synthesized using green chemistry techniques and evaluated for in vitro antifungal activity against Candida albicans and Aspergillus niger.

Result and Discussion:Designed NCE’s (B1-12 and C1-11) showed favorable results in ADMET studies. In the docking study six compounds from series-B and five molecules from series- C showed good dock score and binding interaction when compared with the standard drugs. Compounds B-3 and C-4 showed the highest zone of inhibition activity against Candida albicans, where as B-1 and C-3 had shown highest zone of inhibition activity against Aspergillus niger.

Conclusion:Bicyclic ring (series B) showed better activity as compare to fused tricyclic ring (series C).

Antifungalpyranpyrazolepyrimidinegreen chemistry14-α-demethylasethymidine synthasecytochrome P450.Shafiei M, Peyton L, Hashemzadeh M, Foroumadi A. History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action. Bioorg Chem 2020; 104: 104240. doi: 10.1016/j.bioorg.2020.104240 PMID: 32906036Bongomin F, Gago S, Oladele R, Denning D. Global and multi-national prevalence of fungal diseases—estimate precision. J Fungi 2017; 3(4): 57. doi: 10.3390/jof3040057 PMID: 29371573Banerjee S, Denning D, Chakrabarti A. One Health aspects & priority roadmap for fungal diseases: A mini-review. Indian J Med Res 2021; 153(3): 311-9. doi: 10.4103/ijmr.IJMR_768_21 PMID: 33906993Rayens E, Norris KA. Prevalence and healthcare burden of fungal infections in the United States, 2018. Open Forum Infect Dis 2022; 9(1): ofab593. doi: 10.1093/ofid/ofab593 PMID: 35036461Hussain A, Verma CK. Computational drug repurposing resources and approaches for discovering novel antifungal drugs against candida albicans N-myristoyltransferase. J Pure Appl Microbiol 2021; 15(2): 556-79. doi: 10.22207/JPAM.15.2.49Gohil PB, Ahir RH. Prevalence of fungal infections in patients attending tertiary care teaching hospital, middle gujarat, india. Int J Microbiol Res 2020; 5(3): 364-7.Huang YQ, Tremblay JA, Chapdelaine H, Luong ML, Carrier FM. Pulmonary mucormycosis in a patient with acute liver failure: A case report and systematic review of the literature. J Crit Care 2020; 56: 89-93. doi: 10.1016/j.jcrc.2019.12.012 PMID: 31881411Novais AG, Capelo J, Costa M, et al. Pulmonary mucormycosis: A case report. IDCases 2020; 22: e00993. doi: 10.1016/j.idcr.2020.e00993 PMID: 33240790Choudhary NK, Jain AK, Soni R, Gahlot N. Mucormycosis: A deadly black fungus infection among COVID-19 patients in India. Clin Epidemiol Glob Health 2021; 12: 100900. doi: 10.1016/j.cegh.2021.100900 PMID: 34746515Krishna V, Morjaria J, Jalandari R, Omar F, Kaul S. Autoptic identification of disseminated mucormycosis in a young male presenting with cerebrovascular event, multi-organ dysfunction and COVID-19 infection. IDCases 2021; 25: e01172. doi: 10.1016/j.idcr.2021.e01172 PMID: 34075329Pagano G, García A, Cancino-Abarca S, et al. COVID-19, rejection, and cutaneous mucormycosis in a long-term liver transplant recipient – the vicious cycle of immunosuppression and opportunistic infections. J Liver Transpl 2022; 7: 100113. doi: 10.1016/j.liver.2022.100113Egger M, Bellmann R, Krause R, Boyer J, Jakšić D, Hoenigl M. Salvage treatment for invasive aspergillosis and mucormycosis: challenges, recommendations and future considerations. Infect Drug Resist 2023; 16: 2167-78. doi: 10.2147/IDR.S372546 PMID: 37077251Aswal G, Rawat R, Dwivedi D, Prabhakar N, Kumar KR. Diagnosis and management of mucormycosis in the dental clinic: A guide for oral health professionals in India. J Family Med Prim Care 2022; 11(8): 4293-8. doi: 10.4103/jfmpc.jfmpc_1373_21 PMID: 36353040Gintjee TJ, Donnelley MA, Thompson GR III. Aspiring antifungals: Review of current antifungal pipeline developments. J Fungi 2020; 6(1): 28. doi: 10.3390/jof6010028 PMID: 32106450Wall G, Lopez-Ribot JL. Current antimycotics, new prospects, and future approaches to antifungal therapy. Antibiotics 2020; 9(8): 445. doi: 10.3390/antibiotics9080445 PMID: 32722455Beattie SR, Krysan DJ. Antifungal drug screening: Thinking outside the box to identify novel antifungal scaffolds. Curr Opin Microbiol 2020; 57: 1-6. doi: 10.1016/j.mib.2020.03.005 PMID: 32339892Girois SB, Chapuis F, Decullier E, Revol BGP. Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2006; 25(2): 138-49. doi: 10.1007/s10096-005-0080-0 PMID: 16622909Kanafani ZA, Perfect JR. Antimicrobial resistance: Resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis 2008; 46(1): 120-8. doi: 10.1086/524071 PMID: 18171227Wiederhold N. Antifungal resistance: Current trends and future strategies to combat. Infect Drug Resist 2017; 10: 249-59. doi: 10.2147/IDR.S124918 PMID: 28919789Centre for Disease Control and Prevention. Antimicrobial-Resistant Fungi. 2019. Available from: https://www.cdc.gov/fungal/antifungal-resistance.htmlLiu J, Balasubramanian M. 1,3-beta-Glucan synthase: A useful target for antifungal drugs. Curr Drug Targets Infect Disord 2001; 1(2): 159-69. doi: 10.2174/1568005014606107 PMID: 12455412Rauseo AM, Coler-Reilly A, Larson L, Spec A. Hope on the horizon: Novel fungal treatments in development. Open Forum Infect Dis 2020; 7(2): ofaa016. doi: 10.1093/ofid/ofaa016 PMID: 32099843Mohamed N, Khaireldin NY, Fahmy A, El-Sayed A. Facile synthesis of fused nitrogen containing heterocycles as anticancer agents. Pharma Chem 2010; 2: 400-17.Zida A, Bamba S, Yacouba A, Ouedraogo-Traore R, Guiguemdé RT. Anti- Candida albicans natural products, sources of new antifungal drugs: A review. J Mycol Med 2017; 27(1): 1-19. doi: 10.1016/j.mycmed.2016.10.002 PMID: 27842800Desai NC, Khasiya AG, Jadeja DJ, et al. Synthesis, antifungal ergosterol inhibition, antibiofilm activities, and molecular docking on β-tubulin and sterol 14-alpha demethylase along with DFT-based quantum mechanical calculation of pyrazole containing fused pyridine−pyrimidine derivatives. ACS Omega 2023; 8(41): 37781-97. doi: 10.1021/acsomega.3c01722 PMID: 37867649Tripathi B, Mishra A, Rai P, et al. A green and clean pathway: One pot, multicomponent, and visible light assisted synthesis of pyrano2,3-cpyrazoles under catalyst-free and solvent-free conditions. New J Chem 2017; 41(19): 11148-54. doi: 10.1039/C7NJ01688CAziz H, Zahoor AF, Shahzadi I, Irfan A. Recent synthetic methodologies towards the synthesis of pyrazoles. Polycycl Aromat Compd 2021; 41(4): 698-720. doi: 10.1080/10406638.2019.1614638Mesa-Arango AC, Scorzoni L, Zaragoza O. It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug. Front Microbiol 2012; 3: 286. doi: 10.3389/fmicb.2012.00286 PMID: 23024638Scorzoni L, de Paula e Silva ACA, Marcos CM, et al. Antifungal therapy: New advances in the understanding and treatment of mycosis. Front Microbiol 2017; 8: 36. doi: 10.3389/fmicb.2017.00036 PMID: 28167935Zhang J, Tan D-J, Wang T, Jing S-S, Kang Y, Zhang Z-T. Synthesis, crystal structure, characterization and antifungal activity of 3,4-diaryl-1H-Pyrazoles derivatives. J Mol Struct 2017; 1149: 235-42. doi: 10.1016/j.molstruc.2017.07.106Rastija V, Vrandečić K, Ćosić J, et al. Antifungal activities of fluorinated pyrazole aldehydes on phytopathogenic fungi, and their effect on entomopathogenic nematodes, and soil-beneficial bacteria. Int J Mol Sci 2023; 24(11): 9335. doi: 10.3390/ijms24119335 PMID: 37298285Chi X, Zhang H, Wu H, et al. Discovery of novel tetrazoles featuring a pyrazole moiety as potent and highly selective antifungal agents. ACS Omega 2023; 8(19): 17103-15. doi: 10.1021/acsomega.3c01421 PMID: 37214706Zhao T, Sun Y, Meng Y, et al. Design, synthesis and antifungal activities of novel pyrazole analogues containing the aryl trifluoromethoxy group. Molecules 2023; 28(17): 6279. doi: 10.3390/molecules28176279 PMID: 37687108Ahmad M, Halim A, Mohammed A, Ali Y, Al-Messri Z. Synthesis, characterization and evaluation of some pyranopyrazoles and pyranopyrimidinesderivatives as antioxidants for lubricating oils. Iraqi JSci 2014; 55(1): 1-11.Sagatova AA, Keniya MV, Wilson RK, Monk BC, Tyndall JDA. Structural insights into binding of the antifungal drug fluconazole to saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrob Agents Chemother 2015; 59(8): 4982-9. doi: 10.1128/AAC.00925-15 PMID: 26055382Kapoor JK, Prakash R, Kumar A, Saini D, Arora L. Selective synthesis of 3‐(α,α‐Dibromoacetyl)‐4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one as an excellent precursor for the Synthesis of 2‐substituted 4‐(4‐hydroxy‐6‐methyl‐2 H ‐2‐oxopyran‐3‐yl)thiazoles as antimicrobial and antifungal agents. J Heterocycl Chem 2018; 55(4): 899-906. doi: 10.1002/jhet.3116Sayed GH, Azab ME, Anwer KE. Conventional and microwave‐assisted synthesis and biological activity study of novel heterocycles containing pyran moiety. J Heterocycl Chem 2019; 56(8): 2121-33. doi: 10.1002/jhet.3606Ram VJ, Goel A, Shukla PK, Kapil A. Synthesis of thiophenes and thieno3,2-cpyran-4-ones as antileishmanial and antifungal agents. Bioorg Med Chem Lett 1997; 7(24): 3101-6. doi: 10.1016/S0960-894X(97)10153-6Vala ND, Jardosh HH, Patel MP. PS-TBD triggered general protocol for the synthesis of 4 H -chromene, pyrano4,3- bpyran and pyrano3,2- cchromene derivatives of 1 H -pyrazole and their biological activities. Chin Chem Lett 2016; 27(1): 168-72. doi: 10.1016/j.cclet.2015.09.020Khare SP, Deshmukh TR, Sangshetti JN, Khedkar VM, Shingate BB. Ultrasound assisted rapid synthesis, biological evaluation, and molecular docking study of new 1,2,3-triazolyl pyrano2,3- cpyrazoles as antifungal and antioxidant agent. Synth Commun 2019; 49(19): 2521-37. doi: 10.1080/00397911.2019.1631849Zhao T, Xu LL, Zhang Y, et al. Three new α -pyrone derivatives from the plant endophytic fungus Penicillium ochrochloronthe and their antibacterial, antifungal, and cytotoxic activities. J Asian Nat Prod Res 2019; 21(9): 851-8. doi: 10.1080/10286020.2018.1495197 PMID: 30129376Maddila S, Gorle S, Seshadri N, Lavanya P, Jonnalagadda SB. Synthesis, antibacterial and antifungal activity of novel benzothiazole pyrimidine derivatives. Arab J Chem 2016; 9(5): 681-7. doi: 10.1016/j.arabjc.2013.04.003Ishak C, Metwally N, Wahbi H. In-vitro antimicrobial and antifungal activity of pyrimidine and pyrazolo- 1, 5-a pyrimidine. Int J Pharm Phytopharmacological Res 2013; 2(6): 407-11.Wu W, Lan W, Wu C, Fei Q. Synthesis and antifungal activity of pyrimidine derivatives containing an amide moiety. Front Chem 2021; 9: 695628. doi: 10.3389/fchem.2021.695628 PMID: 34322475Bhagchand J. Prasanta kumarsantra synthesis and evaluation of antimicrobial activity of pyrimidine derivatives. Asian J Pharm Clin Res 2019; 12: 156-63. doi: 10.22159/ajpcr.2019.v12i5.30919Sowdari J, Gudi Y, Donthamsetty SV, Venkatapuram P, Adivireddy P. Green approach for the synthesis of a new class of diamidomethane‐linked benzazolylpyrazoles and evaluation as antifungals. J Heterocycl Chem 2019; 56(8): 2080-9. doi: 10.1002/jhet.3569Shah P. Preparation, characterization, antibacterial, antifungal and antioxidant activities of novel pyrazole-thiazole derivatives. Indian J Chem 2021; 60(9): 1223-9.Becerra D, Abonia R, Castillo JC. Recent applications of the multicomponent synthesis for bioactive pyrazole derivatives. Molecules 2022; 27(15): 4723. doi: 10.3390/molecules27154723 PMID: 35897899Reddy GM, Garcia JR, Zyryanov GV, Sravya G, Reddy NB. Pyranopyrazoles as efficient antimicrobial agents: Green, one pot and multicomponent approach. Bioorg Chem 2019; 82: 324-31. doi: 10.1016/j.bioorg.2018.09.035 PMID: 30415166Makhanya TR, Gengan RM, Kasumbwe K. Synthesis of fused indolo‐pyrazoles and their antimicrobial and insecticidal activities against anopheles arabiensis mosquito. ChemistrySelect 2020; 5(9): 2756-62. doi: 10.1002/slct.201904620El-Assaly SA, Ismail AEHA, Bary HA, Abouelenein MG. Synthesis, molecular docking studies, and antimicrobial evaluation of pyrano2, 3-cpyrazole derivatives. Curr Chem Lett 2021; 10(3): 309-28. doi: 10.5267/j.ccl.2021.3.003Viveka S, Dinesha , Madhu LN, Nagaraja GK. Synthesis of new pyrazole derivatives via multicomponent reaction and evaluation of their antimicrobial and antioxidant activities. Monatsh Chem 2015; 146(9): 1547-55. doi: 10.1007/s00706-015-1428-5Elshaier Y, Barakat A, Al-Qahtany B, Al-Majid A, Al-Agamy M. Synthesis of pyrazole-thiobarbituric acid derivatives: Antimicrobial activity and docking studies. Molecules 2016; 21(10): 1337. doi: 10.3390/molecules21101337 PMID: 27735850Barakat A, Al-Majid AM, Al-Qahtany BM, et al. Synthesis, antimicrobial activity, pharmacophore modeling and molecular docking studies of new pyrazole-dimedone hybrid architectures. Chem Cent J 2018; 12(1): 29. doi: 10.1186/s13065-018-0399-0 PMID: 29541952Sapariya NH, Vaghasiya BK, Thummar RP, et al. Synthesis, characterization, in silico molecular docking study and biological evaluation of a 5-(phenylthio) pyrazole based polyhydroquinoline core moiety. New J Chem 2017; 41(19): 10686-94. doi: 10.1039/C7NJ01962AKathirvelan D, Haribabu J, Reddy BSR, Balachandran C, Duraipandiyan V. Facile and diastereoselective synthesis of 3,2′-spiropyrrolidine-oxindoles derivatives, their molecular docking and antiproliferative activities. Bioorg Med Chem Lett 2015; 25(2): 389-99. doi: 10.1016/j.bmcl.2014.10.099 PMID: 25435149Tummalacharla S, Padmaja P, Reddy PN. An efficient one-pot synthesis of pyrazolyl-thiazolidinedione hybrid analogues and evaluation of their antimicrobial activity. Chem Data Coll 2020; 29: 100507. doi: 10.1016/j.cdc.2020.100507Release S. 2023-1: QikProp. New York, NY: Schrödinger, LLC 2021.QikProp 44 User Manual. LLC, New York: Schrödinger 2015.Charles S, Paul S, Edgar M, Anthony K, Saidi N. The Hunt for antipox compounds against Monkeypox Virus Thymidylate Kinase and scaffolding protein leveraging Pharmacophore modeling, molecular docking, ADMET Studies, and molecular dynamics simulation studies. Research Square 2023. doi: 10.21203/rs.3.rs-3306551/v1Al-Jumaili MHA, Siddique F, Abul Qais F, et al. Analysis and prediction pathways of natural products and their cytotoxicity against HeLa cell line protein using docking, molecular dynamics and ADMET. J Biomol Struct Dyn 2023; 41(3): 765-77. doi: 10.1080/07391102.2021.2011785 PMID: 34861809Vikrama C, Karthikeyan M, Lakshmanan L, et al. Computational study of piper betle l. Phytocompounds by in silico and admet analysis for prediction of potential xanthine oxidase inhibitory activity. Bio Rxiv 2023. doi: 10.1101/2023.01.13.523909Release S. 2023-1: MacroModel. New York, NY: Schrödinger, LLC 2021.Release S. 2023-1: LigPrep. New York, NY: Schrödinger, LLC 2021.Keniya MV, Sabherwal M, Wilson RK, et al. Crystal structure of full-length lanosterol14α-demethylases of prominent fungal pathogens candida albicans and candida glabrata provide tools for antifungal discovery. Antimicrob Agents Chemother 2018; 62(11): e01134-18. PMID: 30126961Amaya JA, Lamb DC, Kelly SL, Caffrey P, Murarka VC, Poulos TL. Structural analysis of P450 AmphL from Streptomyces nodosus provides insights into substrate selectivity of polyene macrolide antibiotic biosynthetic P450s. J Biol Chem 2022; 298(4): 101746. doi: 10.1016/j.jbc.2022.101746 PMID: 35189143Release S. 2023-2: Protein Preparation Wizard; Epik, Schrödinger, LLC, NY, 2023; Impact, Schrödinger, LLC,NY. NY: Prime, Schrödinger, LLC 2023.Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 2013; 27(3): 221-34. doi: 10.1007/s10822-013-9644-8 PMID: 23579614Release S. 2023-1: Glide. NY: Schrödinger, LLC 2021.Friesner RA, Murphy RB, Repasky MP, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006; 49(21): 6177-96. doi: 10.1021/jm051256o PMID: 17034125Friesner RA, Banks JL, Murphy RB, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004; 47(7): 1739-49. doi: 10.1021/jm0306430 PMID: 15027865Halgren TA, Murphy RB, Friesner RA, et al. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004; 47(7): 1750-9. doi: 10.1021/jm030644s PMID: 15027866Mecadon H, Rohman MR, Kharbangar I, et al. l-Proline as an efficicent catalyst for the multicomponent synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano2,3-cpyrazole-5-carbonitriles in water. Tetrahedron Lett 2011; 52(25): 3228-31. doi: 10.1016/j.tetlet.2011.04.048Saleh NM, El-Gazzar MG, Aly HM, Othman RA. Novel anticancer fused pyrazole derivatives as egfr and vegfr-2 dual tk inhibitors. Front Chem 2020; 7: 917. doi: 10.3389/fchem.2019.00917 PMID: 32039146Rodríguez-Tudela JL, Barchiesi F, Bille J, et al. Method for the determination of minimum inhibitory concentration (MIC) by broth dilution of fermentative yeasts. Clin Microbiol Infect 2003; 9(8): i-viii. doi: 10.1046/j.1469-0691.2003.00789.xRuangpan L, Tendencia EA. Laboratory manual of standardized methods for antimicrobial sensitivity tests for bacteria isolated from aquatic animals and environment. In: Tigbauan,. Iloilo, Philippines: Aquaculture Department, Southeast Asian Fisheries Development Center. 2004.