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A series of novel 4-aminoquinolinyl and 9-anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17, 20, and 21 displayed good activity against the 3D7 strain with IC50 values ranging from 19.69 to 25.38 nm. Moreover, compounds 16, 17, 21, 24, 32, and 33 exhibited excellent activities (21.64-54.26 nm) against K1 strain and several compounds displayed β-hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non-toxic with good selectivity index.

An expedient construction of tetrahydro-β-carbolinediketopiperazine ring systems, which are present in various indole alkaloids, is documented. The synthetic strategy proceeds through a Pictet–Spengler reaction followed by an Ugi-4CR and deprotection-cyclization reactions. This is the first report of a Pre-Ugi multicomponent reaction modification using 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylic acid as the acidic partner. This novel approach provides highly diverse reconstructions of novel tetrahydro-β-carbolinediketopiperazine derivatives, which can also be used as privileged structures in medicinal chemistry.

For the first time, an efficient method for the synthesis of tetrazole-isoindoline via palladium-catalyzed cyclization with isocyanide insertion is demonstrated.

Trypanothione reductase (TR) is essential for the survival of the protozoan parasite Leishmania, and, therefore, offers a promising target for the development of selective new drugs against Leishma...

An efficient and mild protocol for rapid access to N-fused polyheterocycles via Pictet–Spengler type 6-endo cyclization using cyanuric chloride in an aqueous reaction medium has been developed. The protocol was successfully applied to a wide range of compounds including aryl/heteroaryl aldehydes (8a–o), ketones (10a–e), an electron-rich metallocene aldehyde (8e) and indoline-2,3-diones (12a–c) using cyanuric chloride (15–20 mol%) with tetra-n-butylammonium bromide (TBAB) (2.0 eq.) as an additive at 80–90 °C to give a good to excellent yield (66–92%) of polyheterocycles. Some of the synthesized compounds were found to exhibit antiplasmodial activity against chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains of Plasmodium falciparum.

A metal-free facile and efficient two-step synthetic protocol for the preparation of 1,4-benzoxazepine-5(2H)-one derivatives has been developed. The protocol involves Ugi reaction followed by K2CO3 mediated highly regioselective 7-exo-dig intramolecular cyclization of less-nucleophilic oxygen with the pendant alkyne moiety of an Ugi–propargyl precursor to afford the 1,4-benzoxazepine-5(2H)-one derivatives in good to excellent yields.

Novel series of 7-piperazinylquinolones with tetrazole derivatives were synthesized and evaluated for their antibacterial activity against various strains of Staphylococcus aureus. All the synthesized compounds showed significant in vitro antibacterial activity against Gram-positive bacteria whereas some compounds displayed moderate activity against Gram-negative bacteria. Among all the synthesized compounds, compounds (6a-c, 6e-g, 6i-k, 6m, 6'f and 6'm) were found to be more effective with MIC ranging from (0.78-3.12 μg/mL) against S. aureus (ATCC-29213) than the control; ciprofloxacin (MIC = 25 μg/mL). Moreover, these analogues displayed no toxicity up to MIC = 0.39 μg/mL against mammalian cell line L-929. Furthermore, to correlate the biological activities of synthesized compounds with their 3D conformation, we attempted 3D-QSAR study.

Most of the synthesized title compounds (III) (19 examples) are found to be active against intracellular amastigote form of Leishmania donovani.

An unusual highly regioselective cascade process is discovered resulting in the conversion of 3-(2-bromophenyl)-2-isopropyl-2,3-dihydroquinazolin-4(1H)-one to a series of 3-substituted derivatives under mild reaction conditions.

The desulfitative dimethylamination of imidazolones (I) is achieved with DMF under optimized microwave conditions.

The title compounds are screened for their antimalarial activities against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum and for their cytotoxicity against VERO cell lines.

The concise and operationally simple two-step protocol allows the synthesis of trans-configurated target compounds (VII) and (IX) with high stereoselectivity.

The reaction of various aromatic amides with isocyanides (II) and (VII) affords isoindolinone derivatives in moderate to good yield and high stereoselectivity.

The present work highlights a synthetic approach to the diverse isoindolinone derivatives using Ugi-4CR followed by a Cu-catalyzed deamidative C–C coupling reaction. This two-step sequence tolerates a broad range of amines, aldehydes, and isocyanides as starting materials for Ugi-4CR products to provide medicinally relevant isoindolinone derivatives in moderate to good yields.

An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at room temperature to afford the desired products in good to excellent yields. In addition, it is interesting to report the subsequent regioselective ring-opening of diketopiperazine unit occurring via an intermolecular transamidation reaction under mild condition, resulting in the formation of highly functionalized indole-2-carboxamides and pyrrole-2-carboxamides.

The conversion of isatoic anhydride (I) to the title heterocycles is investigated under conditions A) and B).

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz–Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.

Several diversity-oriented syntheses of N-fused polycyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually involve time-consuming sequential multistep syntheses, which also suffer from low yields and/or poor precursor scopes. We have developed a new strategy for the syntheses of skeletal diverse N-fused polycyclic compounds via an Ugi-type MCR followed by a CuI-catalyzed coupling reaction or tandem Pictet–Spengler reaction. This two-step sequence provides eight distinct skeleton of fused {6–5–5–6}, {5–5–5–6}, {6–5–6–6}, and {5–5–6–6} ring systems that have applications in medicinal chemistry and chemical genetics too.

Novel fluoroquinolones (I) are synthesized and evaluated for their antibacterial activity against K.

A series of novel chloroquinoline derivatives (I) is synthesized and evaluated in vitro for their antimalarial activity.Compounds (Ic)-(If) exhibit antimalarial potency superior to chloroquine.

The synthetic pathway to β-carbolines (V) and (VII) involves oxidation of educt (I) to its sulfone followed by nucleophilic substitution of the formed mesyl group with tryptamine (II).

Triazinoindoletriazine derivatives (VII) and triazinopyrimidine derivatives (X) are synthesized via cyclization of protected isatin (I) with thiosemicarbazide (II) and nucleophilic substitution of intermediates (V) and (IX) with amines, e.g. (VI).

Regiospecific bromination of benzene derivatives has been carried out with Me2SO–HBr; this method gives excellent yields of 2-bromobenzaldehyde and 2-bromonitrobenzene; strong ortho- and para-directing monosubstituted benzenes give para-bromo derivatives; a general discussion of the mechanism of these reactions is given.

N-alkyiation of primary amines has been carried out with alkylbromide using commercial Me2SO and K2CO3 as a base. This process offers a method of selection for obtaining either mono or dialkyl amines.

Recognizing the potential of combinatorial chemistry to accelerate drug discovery and development, most pharmaceutical and related industries are seriously looking toward combinatorial synthesis of compounds in order to facilitate the identification of 'lead' molecules. In particular, solid phase synthesis is the core technology for combinatorial chemistry and is widely used for generating libraries of structurally related compounds. Since many drugs contain the nitrogen heterocyclic component and since heterocycles possess a high order of structural diversity, a precise overview of recent progress in the combinatorial synthesis of nitrogen heterocycles using solid phase methodology would be useful. Since the progress in solid phase synthesis of organic molecules has been reviewed regularly from 1992 to 1998, only the development of solid phase combinatorial synthetic approaches of small nitrogen heterocycles since 1999 will be reviewed here. This review describes the solid phase synthesis of azepanes, benzodiazepines, benzimidazoles, benzothiazepines, cinnolines, indolizines, beta lactams, oxazepins, oxazoles including benzisooxazoles, hydantoins, piperidines, pyrimidines, pyrazolones, quinolones, trizolopyridazines and thiazoles.

There is challenge and urgency to synthesize cost-effective chemotherapeutic agents for treatment of malaria after the widespread development of resistance to CQ. In the present study, we synthesized a new series of hybrid 9-anilinoacridine triazines using the cheap chemicals 6,9-dichloro-2-methoxy acridine and cyanuric chloride. The series of new hybrid 9-anilinoacridine triazines were evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of Plasmodium falciparum and their cytotoxicity were determined on VERO cell line. Of the evaluated compounds, two compounds 17 (IC(50)=4.21 nM) and 22 (IC(50)=4.27 nM) displayed two times higher potency than CQ (IC(50)=8.15 nM). Most of the compounds showed fairly high selectivity index. The compounds 13 and 29 displayed >96.59% and 98.73% suppression, respectively, orally against N-67 strain of Plasmodium yoelii in swiss mice at dose 100 mg/kg for four days.

In a search for new antiplasmodial agents, a series of thirty five diversely substituted chalcones derived from a quinoline-chalcone scaffold e.g. (E)-3-(2-chloroquinolin-3-yl)-1-(2-hydroxyphenyl) prop-2-en-1-one / (E)-(2-chloro-6-ethoxyquinolin-3-yl) (2-hydroxyphenyl) prop-2-en-1-one and (2Z-3-(2-chloroquinolin-3-yl)-1-(2-hydroxyphenyl)-3-iodoprop-2-en-I-one are synthesized and studied. Compounds are prepared via Claisen-Schmidt condensations of 2-chloro-3-formyl quinoline / 2-chloro-G-ethoxy-3-formyl quinoline with appropriately substituted 2-hydroxy acetophenones. All compounds are assayed for their binding in the active sites of Plasmodium falciparum lactate dehydrogenase (pfLDH) enzyme. The quinoline chalcone derivatives showed negative binding energies promising potent pfLDH inhibitory activity. Compounds showing the highest negative binding scores have been studied for their in vitro antimalarial activity against cultured Plasmodium falciparuna 3D7 strain. The compounds 2c and 2u have completely inhibited the maturation of parasites at MIC 10 μg/mL and above whereas 3b inhibited 95% maturation of parasites at MIC 50 μg/mL. Additional efforts are being directed towards elaborating these leads towards the discovery and development of new quinolinyl heterocycles as anti-malarial agents.

In search of new 4-aminoquinolines which are not recognized by CQR mechanism, thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities. Thiourea derivative 3 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro model with an IC50 of 6.07 ng/mL and also showed an in vivo suppression of 99.27% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.

The emergence and rapid spread of chloroquine resistant strains of Plasmodium falciparum has dramatically reduced the chemotherapeutic options. Towards this goal, a series of new class of hybrid 4-aminoquinoline triazines were synthesized and screened against CQ sensitive strain 3D7 of P. falciparum in an in vitro model. Compounds 65 and 69 exhibited more than 99% suppression on day 4 and on day 6 post treatment, compound 69 showed impressive 99.11% suppression against CQ resistant strain N-67 of P. yoelii in an in vivo assay.

The chemoselective S-alkylation of 2-thiohydantoins is reported. The methodology involves the use of alkyl orthoformates (trimethyl and triethyl) as alkylating agents, which in the presence of Ac2O and ZnCl2 chemoselectively alkylate the thio group whilst other nucleophilic groups present in the thiohydantoins are acetylated simultaneously in moderate to high yields. A plausible mechanism for this reaction is delineated.

A series of marine alkaloid 8,9-dihydrocoscinamide B, its analogues and indolylglyoxylamide derivatives have been synthesized and screened for their in vitro antileishmanial activity profile in promastigote and amastigote models. Compounds 7 and 10 have shown 99–100% inhibition against promastigotes and 97–98% inhibition against amastigotes at a concentration of 10 μg/ml.

A series of triazino tetrahydroisoquinolines ( 3–5 ) and β-carboline derivatives ( 15 – 27 ) have been synthesized as novel antileishmanial agents. Among them, compounds 15 , 16 and 25 have shown 78.0%, 78.6% and 68.0% in vivo inhibition against Leishmania donovani at a dose of 50 mg kg –1 × 5 days, respectively, while compounds 3 and 18 exhibited 55.6% and 53.3% in vivo inhibitions, respectively, against L. donovani at a dose of 50 mg kg –1 × 5 days.

A series of 2,4,6-trisubstituted pyrimidines (3a-o) was synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. Out of the 15 compounds synthesized 11 compounds showed MIC in the range of 0.5-2 microg/mL. These compounds are in vitro several folds more active than pyrimethamine.

A convenient dimethylamino amination of various heterocyclic and aromatic compounds having activated chloro group has been carried out in good yields using dimethyl formamide (DMF).