{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:35:58Z","timestamp":1777415758342,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2\u20136a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10\u201315, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH2 group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16\u201320a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21\u201324a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25\u201330, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi.<\/jats:p>","DOI":"10.3390\/molecules26020368","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T20:11:31Z","timestamp":1610482291000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis of Some New Folic Acid-Based Heterocycles of Anticipated Biological Activity"],"prefix":"10.3390","volume":"26","author":[{"given":"Ola A.","family":"Abu Ali","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-7477","authenticated-orcid":false,"given":"Hosam A.","family":"Saad","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bodor M. A.","family":"Al Malki","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"ref_1","unstructured":"National Center for Biotechnology Information (2016, June 25). PubChem Compound Database; CID\u00bc6037, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/6037."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1172\/JCI104589","article-title":"Interrelations of vitamin B12 and folic acid metabolism: Folic acid clearance studies","volume":"41","author":"Herbert","year":"1962","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0140-6736(02)07439-1","article-title":"Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease","volume":"359","author":"Quinlivan","year":"2002","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"285S","DOI":"10.1093\/ajcn\/85.1.285S","article-title":"Folate and neural tube defects","volume":"85","author":"Pitkin","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2356S","DOI":"10.1093\/jn\/132.8.2356S","article-title":"Folic Acid Supplementation and Prevention of Birth Defects","volume":"132","author":"Green","year":"2002","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1258\/0007142991902646","article-title":"Folic acid deficiency and cancer: Mechanisms of DNA instability","volume":"55","author":"Duthie","year":"1999","journal-title":"Br. Med. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1021\/jm0202369","article-title":"Synthesis of Classical and Nonclassical Partially Restricted Linear Tricyclic 5-Deaza Antifolates","volume":"45","author":"Aleem","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1021\/jo00207a020","article-title":"Synthesis of DL-7,10-ethano-5-deazaaminopterin and L-7,10-ethano-5-deazafolic acid","volume":"50","author":"Edward","year":"1985","journal-title":"J. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1021\/jm00164a033","article-title":"Synthesis and antifolate properties of 10-alkyl-5,10-dideaza analogs of methotrexate and tetrahydrofolic acid","volume":"33","author":"Joseph","year":"1990","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1248\/cpb.43.829","article-title":"Novel 6-5 fused ring heterocycle antifolates with potent antitumor activity: Bridge modifications and heterocyclic benzoyl isosters of 2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine antifolate","volume":"43","author":"Kotake","year":"1995","journal-title":"Chem. Pharm. Bull. (Tokyo)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1002\/jhet.5570310522","article-title":"5-Deaza-7-desmethylene analogues of 510-methylene-5678-tetrahydrofolic acid and related compounds: Synthesis and in vitro biological activity","volume":"31","author":"Andre","year":"1994","journal-title":"J. Heterocycl. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1961S","DOI":"10.1093\/jn\/133.6.1961S","article-title":"Folic Acid Supplements and Fortification Affect the Risk for Neural Tube Defects, Vascular Disease and Cancer: Evolving Science","volume":"133","author":"Bailey","year":"2003","journal-title":"J. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jff.2015.07.018","article-title":"Egg albumin\u2013folic acid nanocomplexes: Performance as a functional ingredient and biological activity","volume":"18","author":"Arzeni","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2174\/156652409787847146","article-title":"Folic acid, neurodegenerative and neuropsychiatric disease","volume":"9","author":"Kronenberg","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2652","DOI":"10.1097\/MD.0000000000002652","article-title":"Folic acid and vitamins D and B12 correlate with homocysteine in Chinese patients with type-2 diabetes mellitus, hypertension, or cardiovascular disease","volume":"95","author":"Mao","year":"2016","journal-title":"Medicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.nutres.2013.01.002","article-title":"Folic acid and vitamin B12 supplementation lowers plasma homocysteine but has no effect on serum bone turnover markers in elderly women: A randomized, double-blind, placebo-controlled trial","volume":"33","author":"Keser","year":"2013","journal-title":"Nutr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/sj.ijo.0803265","article-title":"Effect of short-term folic acid supplementation on insulin sensitivity and inflammatory markers in overweight subjects","volume":"30","author":"Solini","year":"2006","journal-title":"Int. J. Obes."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1161\/CIRCULATIONAHA.107.725481","article-title":"High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury","volume":"117","author":"Moens","year":"2008","journal-title":"Circulation"},{"key":"ref_19","first-page":"980","article-title":"Synthesis of some pyridyloxymethyloxadiazoles, thiazoles and triazoles of expected pharmacological activity","volume":"35B","author":"Saad","year":"1996","journal-title":"Indian J. Chem."},{"key":"ref_20","first-page":"1142","article-title":"Synthesis and Antimicrobial Activity of Some Nitrogen Heterobicyclic Systems: Part II","volume":"37B","author":"Saad","year":"1998","journal-title":"Indian J. Chem."},{"key":"ref_21","first-page":"445","article-title":"Synthesis and antimicrobial activity of some nitrogen heterobicyclic systems: Part I","volume":"38","author":"Allimony","year":"1999","journal-title":"Indian J. Chem. Sec. B Org. Med. Chem."},{"key":"ref_22","first-page":"36","article-title":"Synthesis and Antimicrobial Activity of Some Nitrogen Heterobicyclic Systems: Part III","volume":"39B","author":"Saad","year":"2000","journal-title":"Indian J. Chem."},{"key":"ref_23","first-page":"311","article-title":"Functionlization and Heteroannelation of Ethyl 2-(4\u2032-chlorophenyl)-4-mercapto-6-methylpyrimidine-5-carboxylate","volume":"22","author":"Saad","year":"2001","journal-title":"Bull. Korean Chem. Soc."},{"key":"ref_24","first-page":"277","article-title":"Synthesis of some glycosides of pyridinone derivatives","volume":"59","author":"Saad","year":"2002","journal-title":"AFINIDAD"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.3987\/COM-03-9749","article-title":"Tetrazolo[1,5-b]pyridazine-8-carbohydrazide, Synthesis and some reactions","volume":"60","author":"Deeb","year":"2003","journal-title":"Heterocycles"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3184\/0308234054324002","article-title":"Synthesis of Phenazone Derivatives","volume":"2005","author":"Moustafa","year":"2005","journal-title":"J. Chem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"318","DOI":"10.3184\/030823406777411089","article-title":"Synthesis of Fused heteropolycyclic systems containing an indole moiety","volume":"2006","author":"Saad","year":"2006","journal-title":"J. Chem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1080\/10426500701557286","article-title":"Synthesis of Some New Pyrimidine Derivatives of Expected Antimicrobial Activity","volume":"183","author":"Moustafa","year":"2008","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4937","DOI":"10.3390\/molecules16064937","article-title":"Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties with Expected Pharmacological Activity","volume":"16","author":"Saad","year":"2011","journal-title":"Molecules"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5682","DOI":"10.3390\/molecules16075682","article-title":"Synthesis and Anticancer Activity of Some New S-Glycosyl and S-Alkyl 1,2,4-Triazinone Derivatives","volume":"16","author":"Saad","year":"2011","journal-title":"Molecules"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"573","DOI":"10.2174\/157017912802651447","article-title":"Synthesis of novel fused heterocyclic compounds from 7-amino-[1,2,4]triazino[3,4-b][1,3,4]thiadiazine-8-carbonitrile","volume":"9","author":"Saad","year":"2012","journal-title":"Curr. Org. Synth."},{"key":"ref_32","first-page":"491","article-title":"Synthesis Reactions and Biological Activity of some Triazine Derivatives Containing Sulfa Drug Moieties","volume":"4","author":"Aly","year":"2015","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.2174\/1570179412666141212193009","article-title":"Three-Component Process for the Synthesis of Pyrimido[2,1-c][1,2,4]triazine Derivatives via Knoevenagel Condensation under Thermal Aqueous Conditions","volume":"12","author":"Aly","year":"2015","journal-title":"Curr. Org. Synth."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1016\/j.bmcl.2015.04.096","article-title":"Click reaction based synthesis, antimicrobial, and cytotoxic activities of new 1,2,3-triazoles","volume":"25","author":"Aly","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.3762\/bjoc.11.208","article-title":"Synthesis, antimicrobial and cytotoxicity evaluation of new cholesterol congeners","volume":"11","author":"Aly","year":"2015","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"116","DOI":"10.2174\/1570179412666150511224828","article-title":"Synthesis and Biological Activity of Fused Heteropolycyclic Systems Containing an Indole Moiety","volume":"13","author":"Amin","year":"2016","journal-title":"Curr. Org. Synth."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"408","DOI":"10.2174\/1570179412666150905001956","article-title":"Synthesis and Chemical Behavior of 1,2,4-Triazine Derivatives Bearing\/Containing Phosphorus Amides Donor-Accepto Interactions\u2014A Review","volume":"13","author":"Saad","year":"2016","journal-title":"Curr. Org. Synth."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.3987\/COM-16-13512","article-title":"Thiosemicarbazides, Potent Reagent for Synthesis of Some New 1,4-Diphenylbenzo[g]quinoxaline-5,10-Dione Based Heterocycles","volume":"92","author":"Saad","year":"2016","journal-title":"Heterocycles"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1134\/S1070363216120598","article-title":"Synthesis of Some New Fused 1,2,4-Triazines of Expected Antimicrobial Activity","volume":"86","author":"AlHarthi","year":"2016","journal-title":"Russ. J. Gen. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2174\/1570179413666161008200012","article-title":"Synthesis and Antitumor\/Antiviral Evaluation of 6\u2013Thienyl\u20135\u2013cyano-2\u2013 thiouracil Derivatives and Their Thiogalactosides Analogs","volume":"14","author":"Shehab","year":"2017","journal-title":"Curr. Org. Synth."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4236\/ijoc.2017.71002","article-title":"Cyclocondensation Reactions of Hydrazonoyl Chlorides with Some Azines: Synthesis of New Fused Heterocycles of Expected Microbiological Activity","volume":"7","author":"Mohamed","year":"2017","journal-title":"Int. J. Org. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ali, R.S., and Saad, H.A. (2018). Synthesis of Some Novel Fused Pyrimido[4\u2033,5\u2033:5\u2032,6\u2032][1,2,4]triazino-[3\u2032,4\u2032:3,4][1,2,4]triazino[5,6-b]indoles with Expected Anticancer Activity. Molecules, 23.","DOI":"10.3390\/molecules23030693"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ali, R.S., and Saad, H.A. (2018). Synthesis and Pharmacological Studies of Unprecedented Fused Pyridazino[3\u2032,4\u2032:5,6][1,2,4]triazino[3,4-b][1,3,4]-thiadiazine Derivatives. Molecules, 23.","DOI":"10.3390\/molecules23051024"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/ajcp\/45.4_ts.493","article-title":"Antibiotic susceptibility testing by a standardized single disk method","volume":"45","author":"Bauer","year":"1966","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1128\/jcm.26.8.1437-1441.1988","article-title":"Multicenter evaluation of four methods of yeast inoculum preparation","volume":"26","author":"Pfaller","year":"1988","journal-title":"J. Clin. Microbiol."},{"key":"ref_46","unstructured":"National Committee for Clinical Laboratory Standards (1997). Performance Antimicrobial Susceptibility of Flavobacteria, National Committee for Clinical Laboratory Standards."},{"key":"ref_47","unstructured":"National Committee for Clinical Laboratory Standards (1993). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard M7-A3, National Committee for Clinical Laboratory Standards."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0732-8893(01)00243-7","article-title":"A two-year global evaluation of the susceptibility of Candida species to fluconazole by disk diffusion","volume":"40","author":"Liebowitz","year":"2001","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1128\/AAC.47.5.1647-1651.2003","article-title":"Correlation between E-test, disk diffusion, and microdilution methods for antifungal susceptibility testing of fluconazole and voriconazole","volume":"47","author":"Matar","year":"2003","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:18Z","timestamp":1760159418000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,12]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["molecules26020368"],"URL":"https:\/\/doi.org\/10.3390\/molecules26020368","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,12]]}}}