Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities

Two series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones were designed, synthesised, and evaluated for their antibacterial activities and CDKs inhibitory activities. The pyridazine derivative: 6-phenyl-5-phenylhydrazono-2,3,4,5-tetrahydropyridazine-3,4-dione (3a) revealed activity against Staphylococcus aureus as Gram-positive bacteria while compound 2-(2-Ethoxyphenyl-5-Phenylpiperazinosulfonamido)-3H-pyrido[2,3-d]pyrimidin-4-one (13c) was showing moderate antifungal activity against Candida albicans.     

Synthesis and antimicrobial activity of [6′-methyl-4′-methoxy-2-oxo-2H-[1]-benzopyran)-2″,4″-dihydro-[1″, 2″, 4″]-triazol-3″-one and 3″-phenyl-thiazolidin-4″-one-phenoxymethyl derivatives of dipyranoquinoline

A series of bioactive 3H,7H,8H,11H-9-[(5″-(6′-methyl-2-oxo-2H-[1]-4′-benzopyranoxy)-2″,4″-dihydro-[1″,2″,4″]-triazol-3″-one)methyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (4) and 3H,7H,8H,11H-9-[(2′-(3″-phenyl-thiazolidin-4″-one)-phenoxymethyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (7) analogs of 3H,7H,8H,11H-9-bromomethyl-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (1) have been synthesized and evaluated for their antibacterial activity against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (S. typhi and E. coli). Pyranoquinolines with triazole and thiazolidine moieties exhibited promising antibacterial activity. The structures of all synthesised compounds were confirmed on the basis of analytical and spectral data.     

Synthesis and biological activity studies of new hybrid molecules containing tryptamine moiety

The synthesis of N′-(4-substitutedphenylsulfonyl)-2-{4-[2-(1H-indol-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetohydrazides (3a–c), 2-{4-[2-(1H-indol-3-yl)ethyl]-3-(4-chlorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N′-aryl methylidene acetohydrazides (4a–f) and 4-[2-(1H-indol-3-yl)ethyl]-5-(4-substitutedbenzyl)-2-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a, b) was performed starting from the corresponding acid hydrazides (2a, b) which was reported earlier. The treatment of 1,3,4-oxadiazole derivatives (5a, b) with hydrazine hydrate produced 4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl derivatives (6a, b). Then, compound 6b was converted to the corresponding Schiff base (7) by the treatment with anisaldehyde. The synthesis of 5-(4-chlorobenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (8) and 5-(4-methylbenzyl)-4-[2-(1H-indol-3-yl)ethyl]-2-[(4-benzyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (10) was carried out by the reaction of acid hydrazides (2a, b) with aryl iso(thio)cyanates either via the formation of the intermediates (9a, b) (for 10) or direct cyclization (for 8). 1,3-Oxa(thia)zol-2(3H)-ylidene]acetohydrazide derivatives (11a, b) were obtained by the reaction of 9a, b with 4-chlorophenacyl bromide. All newly synthesized compounds were screened for their antimicrobial activities and some of which was found to be active against the test microorganisms.     

Synthesis of piscidinol A derivatives and their ability to inhibit HIV-1 protease

Four types of piscidinol A derivatives were synthesized and evaluated their ability to inhibit HIV-1 protease to understand their structure-activity relationships. Of these tirucallane-type triterpene derivatives, an A-seco derivative (1b) moderately inhibited human immunodeficiency virus (HIV) protease (IC₅₀ 38.2 μM). The 2,2-dimethyl succinic acid (DMS) acylated tirucallane derivatives (4b, 6a, and 7b, 50 < IC₅₀ < 100 μM) were more inhibitory against HIV-1 PR than the others (PA, 2a, 4a, 4c–4d, 5a, 6b–6d, and 7a, IC₅₀ > 100 μM). These findings indicated that the 2,3-seco-2,3-dioic acid (1b) and DMS-acylated tirucallane-type derivatives preferably inhibited HIV viral protease.     

Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>]azepine derivatives

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.     

Synthesis of benzo[b][1,4]oxazin-3(4H)-ones via smiles rearrangement for antimicrobial activity

The benzo[b][1,4]oxazin-3(4H)-one derivatives, 1a–p, carrying F, Br, and Cl on the benzene ring, or benzyl, cyclohexyl, n-hexyl, and tetrafuryl methylene groups attached to nitrogen atom were synthesized via Smiles rearrangement and assayed in vitro for their antimicrobial activity against Gram-positive, Gram-negative bacteria, and fungi. The antimicrobial activity of the benzo[b][1,4]oxazin-3(4H)-ones showed, on the whole, potency toward all the tested Gram-positive and Gram-negative microorganism (MIC ranging from 16 to 64 μg/ml), whereas weak effectiveness was exhibited against fungi. Data obtained suggest that fluorine atom in the compounds, 1c, 1f, 1i plays an important role in enhancing the antimicrobial properties of this class of compounds. These observations provide some predictions to design further antimicrobial active compounds prior to their synthesis according to molecular modeling studies.     

Microwave assisted synthesis of novel pyrazolone derivatives attached to a pyrimidine moiety and evaluation of their anti-inflammatory, analgesic and antipyretic activities

In the present research work, the motto was to develop new chemical entities as potential anti-inflammatory, analgesic and antipyretic agents. Various 4-(2-amino-6-(substituted)pyrimidin-4-yl)-3-methyl-1-(substituted)-1H-pyrazol-5(4H)-one derivatives (5a–5j) and their Schiff bases (6a–6j) were synthesized. The newly synthesized compounds were characterized by TLC and spectral data. The compounds containing pyrazolone and amino pyrimidine as basic moieties (5a–5j), were screened for their anti-inflammatory, analgesic and antipyretic activities, compounds 5a, 5c–5f, 5h exhibited activities nearly similar to the standard. The pharmacological studies reveal that the presence of 4-hydroxy, 4-methoxy, 4-(N,N-dimethylamino) or 2-hydroxy groups on phenyl ring at C₆ of amino pyrimidine exhibits anti-inflammatory, analgesic and antipyretic activities nearly similar to the standard and substitutions like 4-chloro, 2-nitro, 3-nitro or 4-nitro on same phenyl ring lead to a decrease in activities.     

Synthesis and antimicrobial activity of 1,2,3-triazoles containing quinoline moiety

A new series of substituted 1,2,3-triazoles (4a-n) were synthesized from 4-azido-2,8-bistrifluoromethylquinoline 2. The 1,3-dipolar cycloaddition reaction of 2 with ethyl acetoacetate afforded 1-(2,8-Bistrifluoromethylquinolin-4-yl)-5-methyl-1,2,3-triazole-4-carboxylic acid 3, which was then converted into its corresponding acid hydrazide 3a. Condensation of this hydrazide with different aromatic aldehydes resulted in the formation of Schiff’s bases, N-[1-Arylmethylene]-1-[2,8-bistrifluoromethylquinoline-4-yl]-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (4a-n). These newly synthesized 1,2,3-triazole derivatives were characterized by analytical and spectral data. All the synthesized compounds were evaluated in vitro for their antibacterial and antifungal activity. A brief investigation of the structure activity relationships revealed that the nature of the substituent on position 4 of the triazole ring influences the antimicrobial activity. Among the newly synthesized compounds, the most active compound was 4n, which contained the 3-methylthien-2-yl moiety and showed a broad spectrum of antimicrobial activity against all the strains used for testing. Compounds 4b, 4c, 4e, 4f, 4h and 4l showed significant antimicrobial activity at the concentration of 6.25 μg/mL.     

Synthesis of some new indolo[2,3-c]isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities

A new series of novel compounds [10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]carbohydrazides (3a–c), 1-[10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]fomyl-, -3′,5′-dimethylpyrazoles (4a–c), -3′,5′-diphenylpyrazoles (5a–c), -3′-methylpyrazol-5′-ones (6a–c) and -1′,3′,4′-oxidiazole-2′-thiones (7a–c) linked to indoloisoquinoline at position-6 through formyl bridge was prepared. The structures of these newly synthesized compounds were confirmed by their spectral studies and elemental analysis. These compounds have been screened for their antimicrobial and antioxidant activities. Compounds 4a, 4b, 5a, 5b, 5c, 6b, 7a, and 7c exhibited the maximum zone of inhibition against A. niger, A. flavus, and A. fumigatus. Compounds 4a, 5a, 5c, 6b, 6c, 7a, and 7b showed good antibacterial activity. Compounds 4b, 4c, 5b, 5c, 6a, 6b, 7a, 7b, and 7c showed good radical scavenging activity compared with standards.     

Synthesis and evaluation of in vitro antitubercular activity and antimicrobial activity of some novel 4H-chromeno[2,3-d]pyrimidine via 2-amino-4-phenyl-4H-chromene-3-carbonitriles

Novel 5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dithiones, 5-phenyl-3,5-dihydro-4H-chromeno[2,3-d]pyrimidin-4-ones, 7-phenyl-7,9-dihydro-8H pyrimido[5′,4′:5,6]pyrano[3,2-h]quinolin-8-ones, and 4-amino-5-phenyl-1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2-thiones were synthesized form 2-amino-4-phenyl-4H-chromene-3-carbonitrile. The newly synthesized compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, Mass spectra, and Elemental analysis. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H ₃₇ Rv and antibacterial activity against Staphylococcus Aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as Gram-positive, Escherichia coli [ATCC-25922], and Pseudomonas aeruginosa [MTCC-441] as Gram-negative bacterial strains and antifungal activity against Aspergillus niger [MTCC-282]. Some of these derivatives exhibited pronounced antitubercular and antimicrobial activities.     

Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.     

Design, synthesis and preliminary evaluation of some novel [1,4]diazepino [5,6-b]pyrrolizine and 6-(2-oxopyrrolidino)-1H-pyrrolizine derivatives as anticonvulsant agents

New series of diazepino[5,6-b]pyrrolizines 7a–c and 8a–c and 6-(2-oxopyrrolidino)-1H-pyrrolizines 10a–c were synthesized through acylation of the key aminonitrile derivatives 5a–c (Scheme 1) with the appropriate acid chlorides. Subsequent cyclization reaction yielded the target compounds (Schemes 2, 3). The chemical structure of the synthesized compounds was elucidated by spectral and elemental analyses. The synthesized compounds were evaluated for their ability to protect mice against PTZ-induced seizures, the most active compounds were 10a–c where compound 10b exhibited 67.9% relative potency compared to phenobarbitone and compound 10a provided the maximum protection % of all compounds (60%) at dose of 50 mg/kg comparable to phenobarbitone at a dose of 20 mg/kg.     

A facile synthesis of some 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones and their biological evaluation as anticancer agents

The synthesis of some new 3-cyano-1,4,6-trisubstituted-2(1H)-pyridinones supported with various pharmacophores and functionalities at positin-1 is described. The in vitro anticancer activity of 24 of the newly synthesized compounds was evaluated according to the protocol of the NCI in vitro disease-oriented human cells screening panel assay. The results revealed that five compounds 4a–c, 7b, and 12b were able to display moderate antitumor potential against some of the tested subpanel tumor cell lines at the GI₅₀ and TGI levels, however, with marginal or no cytotoxic (LC₅₀) activity. The obtained data suggested that better antitumor activity was linked to derivatives with either 4-bromophenyl or 3,4-dimethoxyphenyl moieties, together with a 1-methyl-1H-pyrrol-2-yl counter part at positions 6 and 4, respectively. Consequently, the 3-cyano-4-(1-methyl-1H-pyrrol-2-yl)-6-(4-bromophenyl or 3,4-dimethoxyphenyl)-2(1H)-pyridinones 4a and 4b, could be considered as the most active members identified in this investigation as evidenced from their relative higher growth inhibitory (GI₅₀ (MG-MID) 77.6 and 67.6 μM, respectively) and cytostatic (TGI (MG-MID) 85.1 and 95.5 μM, respectively) activities, when compared with the substituted thiocarbamoyl analog 7b and the bicyclic [1,2,4]triazolo[3,4-a]pyridine derivative 12b.     

Synthesis and antimicrobial activity of newer indole semicarbazones

A series of 1-(2-Oxo-2-phenyl-ethyl)-2-phenyl-1H-indole-3yl)methylene) semicarbazone derivatives (4a–g and 6a–c) were synthesized by the condensation of derivatives of 1-(2-Oxo-2-phenyl-ethyl)-2-phenyl-1H-indole-3-carbaldehyde and semicarbazide in ethanol under microwave irradiation procedure. Both conventional and microwave-irradiated syntheses have been carried out to compare their yields and reaction time. The structures of the synthesized compounds were confirmed by spectral data. The antimicrobial activities of the synthesized compounds were screened using broth dilution method. Among all the screened compounds some of the compounds exerted good antifungal activity against C. albicans and C. rugosa. All the compounds exhibited moderate activity against bacteria such as B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeoginosa, and K. pneumoniae.     

SnO2 nanoparticles mediated nontraditional synthesis of biologically active 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]-acridine derivatives

An efficient, practical, and eco-friendly method of preparation of 9-chloro-6,13-dihydro-7-phenyl-5H-indolo[3,2-c]-acridines (3a–c) is reported by Friedlander condensation of 2-amino-5-chlorobenzophenone 1 and active methylene compound 3,4-dihydro-2H-carbazol-1(9H)-ones (2a–c) in the presence of SnO₂ nanoparticles under microwave irradiation. Indoloacridines, 3a–c, were screened for their in vitro hemolytic activity, on human erythrocytes and cytotoxicity, on HeLa and Vero cells.     

Conventional and microwave-assisted synthesis of imidazole and guanidine derivatives and their biological evaluation

A number of imidazole derivatives 3a–f and 4a–f have been synthesized by the condensation of 3-methylthiophen-2-carboxaldehyde 1a, 5-methylthiophen-2-carboxaldehyde 1b, N-methylpyrrol-2-carboxaldehyde 1c, 1-naphthaldehyde 1d, 2-naphthaldehyde 1e, and 2-hydroxy-1-naphthaldehyde 1f with 1,2-diaminoanthraquinone 2a and 2,3-diaminophenazine 2b, respectively. Condensation of 2-guanidinobenzimidazole with functionalized aldehydes 1a–f leads to the formation of guanidine derivatives 5a–f. Both imidazole (3a–f, 4a–f) and guanidine derivatives (5a–f) were synthesized in good yields using conventional heating and microwave irradiation techniques. Structures assigned to compounds 3a–f, 4a–f and 5a–f are supported by correct spectral and analytic data. On screening for anti-inflammatory and anticancer activities, compounds 3e, 4a and 5a exhibited good anti-inflammatory and compounds 3d, 3f, 4d and 4f showed very good anticancer activity.     

CsF�CCelite catalyzed facile N-alkylation of 2(3H)-benzoxazolones and antimicrobial properties of 2-substituted benzoxazole and 3-substituted-2(3H)-benzoxazolone derivatives

The synthesis and antimicrobial activity studies of a new series of cyclic amine containing benzoxazoles and benzoxazolone-2(3H)-ones derivatives were described. The alkylation of benzoxazolone was carried out using cesium fluoride–Celite. The newly synthesized compounds with the influence of the induction of the cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to the antibacterial and antifungal activity. The 2-cyclic amine-1,3-benzoxazoles (5a–l), 5-chloro-3-alkyl substituted-1,3-benzoxazol-2(3H)-ones (8a–f), and 3-[3-(cyclic amine)propyl]-1,3-benzoxazol-2(3H)-ones (9a–f) were synthesized. These derivatives were tested for antibacterial and antifungal activity. Among the compounds tested, 8c and 9f showed moderate to good antibacterial and antifungal activity. Compound 8a showed good antifungal activity.     

Synthesis and anti-HIV evaluation of the novel 2-(m-chlorobenzyl)-4-substituted-7-methyl-1, 1, 3-trioxo-pyrazolo[4, 5-e] [1, 2, 4]thiadiazines

A novel series of 2-(m-Chlorobenzyl)-4-substituted-1, 1, 3-trioxo-2H,4H-pyrazolo[4, 5-e][1, 2, 4] thiadiazines (7a-k) were synthesized, and evaluated for their anti-HIV replication in MT-4 cell cultures. Compound (7a) showed activity against HIV-1-induced cytopathicity, with an EC₅₀ value of 45.6 μM, but none of the compounds exhibited inhibitory activity against HIV-2.     

Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives,their 1,2,4-triazole thioglycosides and acyclic analogs

New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corresponding glycoside derivatives were synthesized. Furthermore, the [)(1,2,4-triazol-3-yl)methyl])-2H-tetrazole derivative as well as the corresponding thioglucoside were prepared. The synthesized compounds were tested for their antimicrobial activity against Aspergillus Niger, Penicillium sp, Candida albican, Bacillus subtilis, Streptococcus lacti, Escherichia coli, Pseudomonas sp., and streptomyces sp. Compounds 3, 5 and 19b exhibited potent antibacterial activity and compounds 4, 5 and 10 exhibited high activities against the tested fungi compared with fusidic acid.