key: cord-1055947-ys4xgqeq authors: Marinescu, Maria title: Biginelli Reaction Mediated Synthesis of Antimicrobial Pyrimidine Derivatives and Their Therapeutic Properties date: 2021-10-04 journal: Molecules DOI: 10.3390/molecules26196022 sha: 7ac3a3daab44483fff06026f4901df0ea6d92f52 doc_id: 1055947 cord_uid: ys4xgqeq Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure–activity relationship in the studied compounds. Twelve years after 1881, the year in which the German Arthur Rudolf Hantzsch reported the multicomponent synthesis of dihydropyridine [1] , in 1893, the Italian chemist Pietro Biginelli published the synthesis of 3,4-dihydropyrimidin-2(1H)-ones, by a simple one-pot condensation reaction of an aromatic aldehyde, urea, and ethyl acetoacetate in ethanol solution (Scheme 1) [2, 3] . Both reactions proved to be "key methods" for the synthesis of pyridine and pyrimidine derivatives, respectively, which were greatly developed in the following period, especially due to the applications of the synthesized compounds. The Biginelli reaction has been intensively studied in the last two decades, especially due to the applications of synthesized dihydropyrimidinone compounds at the beginning, especially as calcium channel blockers of the nifedipine-type [4] , and then as antitumor [5] [6] [7] [8] , antibacterial, antiviral [9, 10] , anti-inflammatory [11, 12] , analgesic [13] , anti-Alzheimer [14] , or antioxidant [15] compounds. The synthetic method initially reported by Biginelli has undergone changes, such as the "Atwal-modification" [4, 5] , and most often, the most efficient catalyst has been sought, which would lead to a higher product yield, milder reaction conditions, and efficient catalyst recovery [16, 17] . In the last decade, several improved methods were reported for Kidwai et al. developed a convenient synthetic route for the preparation of quinazolines 2a-2h by heating equimolar amounts of aldehyde 1a-1d, 5,5-dimethyl-1,3-cyclohexanedione (dimedone), and urea/thiourea in the absence of solvent and catalyst, under microwave irradiation (Scheme 2) [70] . All compounds 2a-2h showed antibacterial activity against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 in the concentration range of 0.564 µg mL −1 when tested by broth microdilution MIC method using norfloxacin as the standard drug. Deshmukh et al. reported an efficient one step synthesis of new 2-amino-5-cyano-6-hydroxy-4-arylpyrimidines 3a-3l by three component Biginelli condensation of aromatic aldehydes, ethyl cyanoacetate, and guanidine hydrochloride in alkaline ethanol (Scheme 3) [71] . All synthesized compounds showed good to excellent activity against tested Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria, but 2-amino-4hydroxy-6-phenylpyrimidine-5-carbonitrile 3d was found to be selectively active against Gram-positive bacteria. Rajanarendar et al. reported Biginelli one-pot condensation of 2-chlorobenzaldehyde, ethyl acetoacetate, and 1-(5-methylisoxazol-3-yl)-3-phenyl thioureas in presence of 10 mol% of ceric ammonium nitrite (CAN) in methanol at 80 • C for 3 h, to obtain isoxazolyldihydropyrimidine-thione carboxylates 4a-4h in 80-90% yields. On heating compound 4 with 3-amino-5-methylisoxazole 5 for 10 h in diphenyl ether at 200 • C under nitrogen atmosphere, new cyclization occurred, yielding 2-thioxo-2,3,6,10b-tetrahydro-1H-pyrimido [5,4c] quinolin-5-one compounds 6a-6h (Scheme 4) [72] . Compounds 6a-6h exhibited moderate to good antibacterial activity against Bacillus subtilis MTCC 441, Bacillus sphaericus MTCC 511, Staphylococcus aureus MTCC 96, Pseudomonas aeruginosa MTCC 741, Klebsiella aerogenes MTCC 39, and Chromobacterium violaceum MTCC 2656, and are more active than the standard drug Ciprofloxacin. The antifungal activity of compounds 6a-6h showed that they are significantly toxic towards all the five tested pathogenic fungi, Aspergillus niger MTCC 282, Chrysosporium tropicum MTCC 2821, Rhizopus oryzae MTCC 262, Fusarium moniliformae MTCC 1848, and Curvularia lunata MTCC 2030, and they are lethal even at a 100 µg mL −1 concentration. However, compounds 6b and 6c exhibited high activity, and they inhibited the growth of fungi to a remarkable extent, which correlated with the presence of methyl and methoxy substituents on the para position of the benzene ring. Chitra et al. reported the synthesis of Biginelli compounds 7a-7h by a one pot cyclocondensation of aldehydes, isopropyl acetoacetate, and urea/thiourea in ethanol, using strontium chloride hexahydrate as the catalyst (Scheme 5) [73] . Generally, the compounds showed moderate-to-good antibacterial activity against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Only 7f, which has a nitro group at the para position, and 7g, which has a fluorine group in the para position, are more active than the reference drug Ciprofloxacin. Additionally, the antifungal activity against Candida albicans, Aspergillus flavus, Rhizopus, and Mucor of compounds 7f and 7g are better than of the standard drug Amphotericin B against all the tested organisms. It is also noted that compounds 7b-7g, which have substituents in the 4-aryl group, are more active than the parent compound 7a against all the tested fungi. Dabholkar et al. reported the one-step synthesis of dihydropyrimidinones 8a-8d and 9a-9d, using a classic Biginelli synthesis, from thiobarbituric acid, aromatic aldehyde, urea/thiourea in ethanol, and a catalytic amount of HCl (Scheme 6) [74] . All synthesized compounds showed good antibacterial activity against Staphyllococcus aureus ATTC-27853, Corynebacterium diphtheria ATTC-11913, Proteus aeruginosa (recultured) and Escherichia coli ATTC-25922 bacterial strains by the disc diffusion method, considering Ampiciline trihydrate as the standard drug. Scheme 6. Synthesis of compounds 8a-8d and 9a-9d. Akhaja et al. proposed a method for the synthesis of 1,3-dihydro-2H-indol-2-ones derivatives 14a-14l in 4 steps: (1) Biginelli synthesis on CaCl 2 catalyst (compounds 10), (2) synthesis of hydrazides 11, by treatment of Biginelli compounds with hydrazine hydrate, (3) cyclization to 1,3,4-thiadiazole 12 in concentrated H 2 SO 4 medium, and (4) condensation with various 5-substituted indoline-2,3-dione 13, in acidic medium, to afford the final compounds 14 (Scheme 7) [75] . Antibacterial activity of all synthesized compounds was screened against Escherichia coli MTCC-443, Pseudomonas aeruginosa MTCC-1688, Klebsiella pneumonia MTCC-109, Salmonella typhi MTCC-98, Staphylococcus aureus MTCC-96, Staphylococcus pyogenus MTCC-442, and Bacillus subtilis MTCC-441, with Gentamycin, Ampicillin, Chloramphenicol, Ciprofloxacin, and Norfloxacin used as standard antibacterial agents; additionally, antifungal activity was screened against three fungal species, C. albicans MTCC 227, Aspergillus niger MTCC 282, and Aspergillus clavatus MTCC 1323, with Nystatin and Griseofulvin as standard antifungal agents. It was found that compounds 14d and 14j (MIC = 62.5-100 µg mL −1 ), containing a strong electron withdrawing group (F), exhibit excellent activity against all bacterial strains, while 14b and 14h (with Br) exhibited comparable activity against Gram-positive strains (MIC = 100-250 µg mL −1 ), and 14c and 14i (with NO 2 ) are highly active against Gram-negative strains (MIC = 100-250 µg mL −1 ), as compared to standard antibiotic Ampicillin. Additionally, compounds 14d and 14f possessed the highest antifungal activity against all fungal strains (100 µg mL −1 ). It was established that the order of decrease in antibacterial activity, depending on the substituent present at the 5th position of 1H-indole-2,3-diones, is F > NO 2 > Br > Cl > H. Kamal Table 1 lists the compounds with the best antibacterial activity on at least three tested strains. We note that the ethylated compounds "b" are more biologically active. Kulakov synthesized new 3,4-dihydropyrimidin-2-thiones 28 in two steps: (i) a Biginelli reaction to obtain compounds 27 and (ii) an aminomethylation Mannich reaction to obtain 3,4-dihydropyrimidin-2-thiones grafted with alkaloid cytisine (Scheme 9) [78] . The bioscreening of 28a revealed its pronounced antibacterial activity against the Gram-positive strains S. aureus and B. subtilis, weak activity against Gram-negative strains P. aeruginosa and E. coli, in addition to the fungus C. albicans. Table 2 . Compound 31e, which possesses two chlorine atoms, has the best antimicrobial activity at 12.5 µg mL −1 against all tested strains. Scheme 10. Synthesis of compounds 31a-31n. Youssef and Amin synthesized new compounds 37a-37b and 38a-38b, using Biginelli intermediates 36a-36b obtained by a classical reaction (Scheme 12) [81] . The newly heterocyclic compounds were tested for their antimicrobial activity against Escherichia coli, Pseudomonas putida, Bacillus subtilis, Streptococcus lactis, Aspergillus niger, Penicillium sp., and Candida albicans. All compounds showed moderate to slight inhibitory action towards the microorganisms. Umesha et al. synthesized in two steps compounds 47a-47f and 48a-48f (Scheme 15) [85] . Compound 48c showed the best antimicrobial activity against all tested strains, four bacterial strains, S. aureus, B. subtilis, S. typhi, and E. coli, and two fungal strains, A. niger and C. albicans, but the other compounds also had good antimicrobial activities. The antibacterial screening results revealed that acetyl-substituted pyrimidinone compounds 49c and 49f showed a broad spectrum of antimicrobial activity against E. coli, P. aeruginosa, and K. pneumonia (6.25 µg mL −1 ), comparable with the standard Streptomycin (6.25 µg mL −1 ). A gradual decrease in the activity against the tested strains was noticed, with the introduction of ethoxy 49a and 49d and methoxy 49b and 49e groups, in place of acetyl substituent. Raj et al. reported the synthesis of dihydropyrimidinones 50a-50e, by a Biginelli reaction using Zn(ClO 4 ) 2 as catalyst (Scheme 17) [87] . In vitro antibacterial studies of dihydropyrimidones 50a-50e were carried out against Escherichia coli MTCC 119, Shigella flexneri MTCC 1457, Pseudomonas aeruginosa MTCC 741, and Staphylococcus aureus MTCC 740 strains, by disk-diffusion assay. Antifungal evaluations were also carried out against two fungal strains, Geotrichum candidum MTCC 3993 and Candida albicans MTCC 227 (Table 3) . From the determined MIC values, it can be said that compound 50a had the best antimicrobial activity against all the strains tested. Ahmad et al. reported the synthesis of some 2-amino-1,4-dihydropyrimidines by a Biginelli reaction, starting from guanidine HCl, benzaldehyde, and ethyl acetoacetate in DMF, and SnCl 2 ·2H 2 O or NaHCO 3 as catalyst, under ultrasonic irradiation [90] . The good antibacterial activities of compounds 64, 65, and 66 ( Figure 5 ), against S. aureus, B. subtilis, E. coli, and S. typhi, as well as the theoretical studies, have shown that these compounds may have acceptable pharmacokinetic/drug-like properties. [91] . All the synthesized compounds exhibited significant activity against pathogenic bacteria Salmonella typhi and Staphylococcus aureus. These dihydropyrimidinone (DHPM) derivatives also focus on the bacterial ribosomal A site RNA as a drug target. Series of docking studies were also performed for human 40S rRNA as a target. It was found that amikacin drug exhibited higher binding affinity than compound 68e, which showed relatively low binding affinity towards human rRNA site ( Figure 6 ). Desai and Bhatt reported the synthesis of compounds 72a-72c, using, in the first step, a Biginelli reaction in the presence of SnCl 2 ·2H 2 O catalyst to obtain compound 69, which, in the presence of hydrazine hydrate, resulted in a hydrazide 70, from which Schiff bases 71a-71c were obtained by reaction with aromatic aldehydes. Cyclization of compounds 71 in the presence of triethylamine provided the desired β-lactams 72a-72c, as shown in Scheme 20 [92] . Compounds 72a-72c exhibited outstanding antimicrobial properties against almost all tested strains S. aureus, S. pyogenes, E. coli, P. aeruginosa, C. albicans, A. niger, and A. clavatus with MIC = 12.5-50 µg mL −1 for antibacterial activities and 25-100 µg mL −1 for antifungal activities, respectively. Thus, bis-derivatives 75a-75b were found to be more efficacious than their corresponding mono analogues 74a-74b. Compound 75b with two pyrimidithione rings showed high synergy with amphotericin-B and fluconazole, both followed by compounds 75a, 74b, and 74a. Rani et al. synthesized compounds 76a-76e by a Biginelli reaction from 3-oxo-Nphenylbutanamide, guanidine nitrate, an aldehyde, and HCl as catalyst [95] (Scheme 21), and compounds 77a-77e, from the reaction of derivatives 76 with 6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol, ethyl acetoacetate, and monochloroacetic acid. It was found that compounds 77a and 77b had significant activity against S. aureus (MIC = 2.14 × 10 −2 µM mL −1 ), and compound 77c was most potent against B. subtilis (MIC = 0.58 × 10 −2 µM mL −1 ). Compound 77e displayed more potent activity against E. coli (MIC = 1.10 × 10 −2 µM mL −1 ), and compound 77d was found to be most potent against C. albicans and A. niger (MIC = 1.04 × 10 −2 µM mL −1 ). (Table 4 ). All compounds exhibited excellent antibacterial activity against S. aureus -bold values (MIC = 0.2-6.25 µg mL −1 ), but in the case of B. subtilis, all compounds were less active. The efficacy of substituent at C-6 position decreased in the order -CH 3 > -7,8-Benzo > -Cl > -OCH 3 (b > e > c >a). Similarly, compounds 81a, 81c, and 81e were highly active against E. coli, whereas the other compounds showed significantly less activity. Synthesis of compounds 80a-80e and 81a-81e. Hamdi et al. synthesized 3,4-dihydropyrimidinones 82a-82e by a modified Biginellitype reaction with various metallophthalocyanines 83-85 as reusable heterogeneous as catalysts ( Figure 9 ) [99] . The antimicrobial activity of compounds 82a-82e was evaluated against Micrococcus luteus LB 14110, Staphylococcus aureus ATCC 6538, Listeria monocytogenes ATCC 19117, and Salmonella typhimurium ATCC 14028, but significant antimicrobial activity (MIC = 312 µg mL −1 ) was observed against M. luteus. Youssef et al. synthesized 6-amino-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5carbonitrile derivatives 86a-86d by Biginelli reaction of aromatic aldehydes, malononitrile, and thiourea in alcoholic sodium ethoxide solution [100] . The reaction of each 86 with monobromomalononitrile in ethanolic potassium hydroxide solution yielded, in each case, a single product, 87a-87d. By refluxing each 87 with carbon disulphide, the corresponding compounds 88a-88b were obtained. Finally, heating compounds 87 with formic acid yielded 89a-89b ( Figure 10). Compounds 86a, 86b, 87a, 87b, 88a, and 89a showed moderate to slight inhibitory action against the tested strains Escherichia coli, Pseudomonas putida, Bacillus subtilis, Streptococcus lactis, Aspergillus niger, Penicillium sp., and Candida albicans. Table 5 , compounds 92a-92c show good antibacterial activity against all the tested species (MIC = 3.12-25 µg mL −1 ). Scheme 23. Synthesis of compounds 90a-90c and 92a-92c. (Table 6 ). Compound 97d displayed inhibitory efficacies and a broader antibacterial spectrum than that of the reference drugs. Compound 97d exhibited excellent inhibiting activity than the standard streptomycin (MIC = 6.25 µg mL −1 ) and equipotent to that of penicillin (MIC = 1.562 µg mL −1 ) against S. aureus and B. subtilis with MIC values 1.56 µg mL −1 , being almost as active as the standard drug (MIC = 3.12 µg mL −1 ) against Gram-positive S. epidermidis (MIC = 3.12 µg mL −1 ). Compounds 97c and 97e could effectively inhibit the growth of S. aureus with MIC values (MIC = 1.56 and 3.12 µg mL −1 , respectively) and P. aeruginosa (MIC = 6.25 µg mL −1 ). Compounds 97a, 97b, 97c and 97e have shown bioactivity against P. aeruginosa (MIC = 6.25 µg mL −1 ), which was better than penicillin. Compounds 97g and 97h showed significant activity against S. aureus (MIC = 3.12 µg mL −1 ). New selenoxotetrahydropyrimidines 98a-98g were synthesized by Biginelli reaction of ethyl acetoacetate, substituted aromatic aldehydes and selenourea (Scheme 25) in ethanol in the presence of HCl under microwave irradiation [104] . The results of antibacterial evaluation indicated that compounds 98a and 98e are active against Gram-positive bacteria Pseudomonas fluorescens, while compounds 98b and 98d exhibited significant an-tibacterial activity against Gram-negative bacteria Klebsellia pneumoniae and Escherichia coli, respectively (Table 7) . Only compound 98f was active against both Gram-negative and Gram-positive strains, namely Pseudomonas aeruginosa and Staphylococcus pyrogens. Additionally, compounds 98c and 98g possessed antifungal activity against Aspergillius janus and Penicillium glabrum. In conclusion, all compounds showed inhibitory effects with a minimum inhibitory concentration of 8 µg mL −1 . Synthesis of compounds 98a-98g. Gein et al. reported that reaction of dimedone with a mixture of 5-aminotetrazole monohydrate and substituted aromatic aldehyde taken in an equimolar ratio without solvent and catalyst at a temperature of 160-170 • C for 5-10 min afforded 9-aryl-6,6-dimethyl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-ones 101 ( Figure 12 ) [106] . All compounds were found to have low antibacterial and antifungal activity (MIC > 1000 µg mL −1 ). Jadhav et al. reported the diisopropyl ethyl ammonium acetate (DIPEAc)-promoted Biginelli protocol by a successive one-pot three-component reaction of aldehydes, ethylcyanoacetate/ethyl acetoacetate, and thiourea/urea to afford pharmacologically promising 1,2,3,4-tetrahydropyrimidines in high yields at room temperature [108] . All compounds were evaluated against four bacterial Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and two fungal Candida albicans, Aspergillus niger strains with Ampicillin and Griseofulvin as standard drugs . Compounds 103a, 103b, and 103c showed satisfactory antibacterial activity against all four bacterial pathogens due to the presence of withdrawing groups (-NO 2 and -CF 3 ) and electron-donating groups (-OH and -OCH 3 ) in the molecule ( Figure 13 , Table 8 ). In addition, 103b showed good antibacterial activity against the Gram-positive strains, P. aeruginosa, E. coli, S. aureus, and S. pyogenes, which can be significantly correlated with the presence of -OH and -OCH 3 groups in the molecule. Additionally, compounds 103d, 103e, and 103f showed potent activities against all the tested fungal strains. The best antimicrobial values are marked in bold in Table 8 . of compounds 104a, 104b, and 104c showed the best activity (of all compounds -bold values) against all tested strains (Table 9 ). Scheme 28. Synthesis of compounds 104a-104c. New 1,2,3,4-tetrahydropyrimidines 105 were synthesized by Biginelli reaction starting from the desirable aldehyde, benzyl 3-oxobutanoate, urea, and Co(HSO 4 ) 2 (Scheme 29) [110] . Antibacterial activity of the compounds was tested against bacterial strains S. aureus, P. aeruginosa, E. coli and S. flexneri. Compounds 105a-105d showed significant growth inhibition at 40.6, 21.7, 37.8, and 19.9 µg mL −1 concentrations, respectively, against S. aureus and maximum activity at 34.0, 17.8, 101.4, and 52.4 µg mL −1 , respectively, against E. coli. Rajitha et al. synthesized new 3-substituted 5-phenylindeno-thiazolopyrimidinones in two steps (Scheme 30) [111] . The first reaction is a poly(4-vinylpyridinium)hydrogen sulfate catalyzed Biginelli reaction to produce 106, and the second is a condensation with phenacyl bromide to give 107. Among the analogs, 4-methoxyphenyl-5-phenylindeno[1,2-d]thiazolo [3,2-a]pyrimidin-6(5H)-one showed good activity against a bacterium, Staphylococcus aureus (MIC = 25 µg mL −1 ), and a fungus, Aspergillus niger (zone of inhibition 20 mm). Sethiya et al. reported the eco-friendly synthesis of pyrimidine derivatives 108a-108g by the reaction of aromatic aldehydes, 2-aminobenzothiazole and dimedone in the presence of thiamine hydrochloride (Vitamine B 1 ) as organocatalyst (Scheme 31) [112] . Molecular docking studies were performed on the synthesized compounds using Staphylococcus aureus dihydropteroate synthase (saDHPS) (6CLV) and DNA gyrase (1KZN) proteins. Compound 108e was found to be the most potent and showed good binding interactions and the highest docking score against both proteins, 1KZN and 6CLV (Figure 14) . A series of 3,4-dihydropyrimidin-2(1H)-thione compounds were synthesized from the 1-(4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro pyrimidin-5yl)ethanone 109, as can be seen in Scheme 32 [113] . Compounds 110b, 111b, 112, and 113b were the most potent against the tested microorganisms Staphylococcus aureus AUMC B.54, Bacillus cereus AUMC B.52, Escherichia coli AUMC B.53, Pseudomonas aeruginosa AUMC B.73, Candida albicans AUMC 214, and Aspergillus flavus AUMC 1276 (Table 10 ). It was stated that presence of certain electron donating groups, such as -Cl and -OCH 3 , may increase the antimicrobial activity of the compounds. These results are in line with similar results in the literature [114, 115] . of compounds 109, 110a-110c, 111a, 111b, 112, 113a , and 113b. Tuberculosis, resulting from infection by the bacterium Mycobacterium tuberculosis, is a major worldwide health problem [116] . Approximately 2 million people die every year. The emergence of multi-drug resistance has forced the development of new structural classes of antitubercular agents, with several of them showing promising activity against M. tuberculosis [117] . Virsodia et al. synthesized new N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides using the Biginelli reaction by reacting acetoacetanilide derivatives, substituted aldehydes, and urea in methanol with a catalytic amount of HCl. Compound 114 showed 65% inhibition of M. tuberculosis, the best antitubercular activity ( Figure 15 ). Additionally, 3D-QSAR studies are reported. Trivedi et al. reported the synthesis of 30 dihydropyrimidines by a classical Biginelli reaction and their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv [118] . Two compounds, 115a and 115b, with MIC of 0.02 µg mL −1 against M. tuberculosis, were found to be the most active of all and more potent than isoniazid. Akhaja et al. found that compound 14d displayed promising antitubercular activity compared to standards Rifampicin and Izoniazid [75] . Yadlapalli implemeted a Biginelli reaction for the synthesis of 4-aryl-3,4-dihydro-2(1H)-pyrimidone esters possessing lipophilic carbamoyl groups [120] . Compounds 117a and 117b, with a MIC value of 0.125 and 0.25 µg mL −1 , were found to be the most potent in the series ( Figure 16 ). Ambre et al. reported the synthesis of 16 compounds, 4-(substituted) phenyl-2-thioxo-3,4-dihydro-1H-chromino [4,3-d] pyrimidin-5-one and 4-(substituted) phenyl-3,4-dihydro-1H-chromino [4,3-d] pyrimidine-2,5-dione analogs as antitubercular agents by a classical. Biginelli reaction between a substituted aldehyde, 6substituted-4-hydroxy coumarin, urea (or thiourea), and p-toluenesulfonic acid as catalyst. Compounds 118a and 118b, with MIC of 59% and 61%, respectively, were found to be the most potent in these series [121] . It was found that compounds 119a-119d exhibited an MIC between 0.08 and 0.09 µM, which is found to be better than the standard reference Isoniazid with MIC of 0.2 µM. The very good antitubercular activity was correlated with the presence of the fluorine atom in the molecule. Scheme 34. Synthesis of compounds 119a-119d. Youseff et al. found that compounds 37a and 37b showed considerable inhibitory activity in the hemolysis assay (Table 11 ) [81] . Compounds 37c and 37d ( Figure 17 ) showed moderate antioxidant and inhibitory activity (Table 12) . Additionally, the antioxidant assay by ABTS method showed that compounds 37a, 37b, 37c, and 37d showed potent antioxidant activity. [86] . Attri et al. reported that that compounds 73a-73c possess good-to-moderate antioxidant activity in comparison to the standard gallic acid and quercetin [93] . Rani et al. reported that compounds 77f and 77g exhibited excellent in vitro antioxidant activity due to the presence of electron releasing groups on benzylidene portion ( Figure 18 ) [95] . Yadlapalli reported that compound 117a, with excellent antitubercular activity against MTB H37Rv, showed moderate anticancer activity against MCF-7 breast cancer cell lines [120] . Compound 77h was found to be the most potent anticancer agent (IC 50 Gelatinases are present in the physiologic system and play a key role in inflammation and autoimmunity states. Activated inflammatory cells and dermal fibroblasts can express several proteinases designated as matrix metalloproteinases (MMPs) able to degrade all connective tissue macromolecules [98] . Among these are gelatinases, e.g., MMP-2 and MMP-9, which, together with interstitial collagenase, have been assumed to be of importance in connective tissue remodeling after inflammation. The obtained results revealed that all compounds 80a-80e and 81a-81e were highly active against MMP-2 (72 kDa gelatinase A). Similarly, the compounds 80e, 81a, 81b, 81d, and 81e were highly active against MMP-9 (92 kDa gelatinase B), whereas the compounds 80b and 80d showed slight inhibitory activity, and rest of the compounds were not active against MMP-9 (Table 13 ). [79] . From the anti-inflammatory activity result analysis, Viveka et al. observed that compounds 92a, 92b, 92d, 92e, 92f, 92g, and 92h showed good activity, with 67.61 to 85.33% inhibition of the edema (Figure 19 ). The compounds 92a (85.33) , 92d (81.32) , and 92h (80.75) showed potent anti-inflammatory activity compared with the other test compounds and are comparable with the standard, indomethacin (86.76) . This emphasizes the presence of the 3F-4CH 3 -substituted phenyl ring on the 5th position of the 3-oxothiazolopyrimidine nucleus in this pyrazole series [101] . Additionally, El-Emary et al. found that compounds 110b and 112b (Scheme 29) had the most anti-inflammatory activity, comparable to that of Indomethacin [113] . Alam et al. reported that compounds 31c, 31d, and 31e with analgesic activity (expressed as % protection) of 44.35%, 47.01%, and 50.36%, respectively, have analgesic properties, considering Indomethacin as the standard (60.30%) [79] . Khalifa Figure 21A ). Compound 4a exhibited at least three different long-distance hydrogen-bond interactions. An O1 atom showed with the NH 2 atom of Arg259 with a distance of 3.06 Å, an O3 atom showed with the NE2 atom of His93 with a distance of 2.87 Å, and a Cl atom showed with the O atom of Pro69 with a distance of 2.87 Å ( Figure 21B ). Additionally, other atoms of the molecule showed several important hydrophobic interactions against Asp256, Asn94, Met414, Asp71, and Tyr411 with different distances. These results showed that the relatively higher antiviral activity of compound 48a than 47a may due to lower docking and binding energies, as well as higher hydrogen and hydrophobic interactions. Rajanarendar reported that compounds 6b and 6d are proved to be lethal for mosquito larvae, with LC 50 concentration, representing the concentration in ppm that killed 50%, of 0.85 and 0.88, respectively (Scheme 4) [72] . Thus, pyrimidine compounds 6b and 6d can be useful as more toxic substances to kill mosquito larvae. Fatima et al. reported the synthesis of three Biginelli compounds 120, 121, and 122 more potent than the standard drug Chloroquine against K1 strains of P. falciparum, with an IC 50 (µg mL −1 ) of 0.56, 0.5 and 0.5, respectively ( Figure 23 ) [123] . These compounds with three different pharmacophores have potential to be exploited in medicinal chemistry. This review summarizes the recent Biginelli syntheses of pyrimidine compounds with antimicrobial properties, as well as their biological activities mentioned in the literature. Regarding the Biginelli synthesis of pyrimidine compounds, the presentation clearly shows that the catalyst has an important role in the development of the reaction and in obtaining a high yield. Derivatization of Biginelli compounds leads in most cases to compounds with stronger antimicrobial properties than the initial Biginelli dihydropyrimidines. Additionally, the presence of another heterocycle in the final molecules, such as pyrazole, thiazole, isoxazole, imidazole, benzothiazole, phenothiazine, 1,3,4-thiadiazole, coumarin, chromene, indole, and quinoline, potentiate the antimyrobial activity of pyrimidine compounds. In general, thiopyrimidine compounds have a stronger antimicrobial activity than pyrimidinone compounds. Selenopyrimidine compounds generally have better antimicrobial activity than pyrimidinone. Additionally, the presence of certain groups grafted on the benzimidazole and pyrazole nuclei, such as -NO 2 , -CN, -F, -CF 3 , -CN, -COOCH 3 , -NHCO, -CHO, Cl, -OH, OCH 3 , OC 2 H 5 , and -N(CH 3 ) 2 , increases the antimicrobial activity of the compounds [124] [125] [126] [127] . However, there are quite a few studies performed on the structureproperties relationship for these compounds, as well as few studies of molecular mechanics, DFT, through which to achieve the directed synthesis of some biologically active molecules. Therefore, we hope that this article will be a starting point for conducting new theoretical studies and syntheses of new compounds for the synthesis of improved antimicrobial compounds that possess other biological activities. 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The author declares no conflict of interest.