Prem M.S. Chauhan

Cyanuric Chloride Catalyzed Mild Protocol for Synthesis of Biologically Active Dihydro/Spiro Quinazolinones and Quinazolinone-glycoconjugates

We have developed an efficient cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, TCT) catalyzed approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-one (3a-3x), 2-spiroquinazolinone (5, 7), and glycoconjugates of 2,3-dihydroquinazolin-4(1H)-one (10a, 10b) derivatives. The reaction allows rapid cyclization (8-20 min) with 10 mol % cyanuric chloride to give skeletal complexity in good to excellent yield. We believe that this novel procedure may open the door for the easy generation of new and bioactive quinazolinones.

Discovery of a New Class of Natural Product-Inspired Quinazolinone Hybrid as Potent Antileishmanial agents

The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.2 to 7.76 ± 2.1 μM) as compared to miltefosine (IC50 = 8.4 ± 2.1 μM) and nontoxic toward the J-774A.1 cell line and Vero cells. Moreover, activation of Th1 type and suppression of Th2 type immune responses and induction in nitric oxide generation proved that 8a and 8g induce murine macrophages to prevent survival of parasites. Compounds 8a and 8g exhibited significant in vivo inhibition of parasite 73.15 ± 12.69% and 80.93 ± 10.50% against Leishmania donovani /hamster model. Our results indicate that compounds 8a, 8g, and 9f represent a new structural lead for this serious and neglected disease.

Bis and tris indole alkaloids from marine organisms: new leads for drug discovery.

The marine organisms are a rich source of varied natural products with unique functionality. Marine natural products chemistry has undergone an explosive growth during the past three decades. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna, thus ensuring motivation in the search of newer natural products. The bis and trisindole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. 3-hydroxy staurosporine 51, an indolo carbazole having powerful antiproliferative activity. Hamacanthin A 1 and B 2, pyrazinone alkaloids have significant antimicrobial activity. Coscinamides 60-62 and Chondriamides 63-65 an indolic enamides which have anti-HIV and cytotoxic activity respectively. Gelluisine A 66 and B 67, trisindole alkaloids have strong anti-serotonin activity and strong affinity with somatostatin and neuropeptide Y receptors in receptor-binding assays. This report reviews the literature on these alkaloids of marine origin and highlights the isolation, structure, latest synthesis and specific biological activities including cytotoxicity, antiviral, antiparasitic, serotonin antagonism and other pharmacological activities of sixty-nine bis and trisindole alkaloids.

A Ligand-Free Pd-Catalyzed Cascade Reaction: An Access to the Highly Diverse Isoquinolin-1(2H)-one Derivatives via Isocyanide and Ugi-MCR Synthesized Amide Precursors

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.

Substituted quinolinyl chalcones and quinolinyl pyrimidines as a new class of anti-infective agents.

Frequency of tuberculosis and malaria is progressively increasing worldwide. New emerging strain of bacterium and resistance to currently available drugs make this field more conscientious and alarming. In this connection a series of substituted quinolinyl chalcones and substituted quinolinyl pyrimidines were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H(37)R(V) and antimalarial activity against NF-54 strain of Plasmodium falciparum. A comparison of structure-activity relationship reveals that different physicochemical and structural requirements exist for these two activities. Out of synthesized compounds, compound nos. 22 and 23 have shown antitubercular activity of MIC 3.12 microg/mL and were nontoxic against VERO, MBMDM cell lines and compounds 54, 55, and 56 have shown antimalarial activity of MIC 1 microg/mL.

Synthesis and bioevaluation of hybrid 4-aminoquinoline triazines as a new class of antimalarial agents.

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.

Synthesis of new 4-aminoquinolines and quinoline-acridine hybrids as antimalarial agents.

Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modified 4-aminoquinoline derivatives and quinoline-acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC=0.125 μg/mL) was equipotent to standard drug CQ (MIC=0.125 μg/mL) and compound 21 (MIC=0.031 μg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4-aminoquinoline class for new antimalarials.

Synthesis of novel thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials

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 IC(50) of 6.07ng/mL and also showed an in vivo suppression of 99.27% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.

Synthesis of 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-β-carbolines as a new class of antimalarial agents

A series of hybrid molecules 2-[3-(7-Chloro-quinolin-4-ylamino)-alkyl]-1-(substituted phenyl)-2,3,4,9-tetrahydro-1H-beta-carbolines have been synthesized and screened for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. Compounds 26, 32, and 34 have shown MIC in the range of 0.05-0.11 microM and are in vitro several folds more active than chloroquine.

Synthesis of oxalamide and triazine derivatives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activity

Frequency of malaria and its resistance to chemotherapeutic options are emerging rapidly. To counter this problem, a series of 4-aminoquinolines having oxalamide and triazine functionalities in the side chain were synthesized and screened for their antimalarial activities. Triazine derivative 48 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro assay with an IC(50) of 5.23 ng/mL and oxalamide derivative 13 showed an in vivo suppression of 70.45% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.