Sunny Manohar

Novel 4-aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity.

A class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Eleven hybrids showed better antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum in comparison to standard drug CQ. Four molecules were more potent (7-8-fold) than CQ in D6 strain, and eight molecules were found to be 5-25-fold more active against resistant strain (W2). Several compounds did not show any cytotoxicity up to a high concentration (60 μM), others exhibited mild toxicities, but the selective index for the antimalarial activity was very high for most of these hybrids. Two compounds selected for in vivo evaluation have shown excellent activity (po) in a mouse model of Plasmodium berghei without any apparent toxicity. The X-ray crystal structure of one of the compounds was also determined.

Synthesis, antimalarial activity and cytotoxicity of 4-aminoquinoline-triazine conjugates.

A series of 4-aminoquinoline-triazine conjugates with different substitution pattern have been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum. Compounds 16, 19, 28 and 35 exhibited promising antimalarial activity against both strains of P. falciparum. Cytotoxicity of these compounds was tested against three cell lines. Several compounds did not show any cytotoxicity up to a high concentration (48microM), others exhibited mild toxicities but selective index for antimalarial activity was high for most of these conjugates.

Synthesis of 4‐aminoquinoline‐1,2,3‐triazole and 4‐aminoquinoline‐1,2,3‐triazole‐1,3,5‐triazine Hybrids as Potential Antimalarial Agents

We report herein synthesis of a series of 4‐aminoquinoline‐1,2,3‐triazole and 4‐aminoquinoline‐1,2,3‐triazole‐1,3,5‐triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure–activity relationship of substituted 4‐aminoquinoline–based hybrids, 34 structurally diverse compounds were synthesized and tested against D6 and W2 strains of P. falciparum. Some of the compounds have shown promising antimalarial activity without toxicity against Vero cells.

Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC(50) values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.

4-aminoquinoline-triazine-based hybrids with improved in vitro antimalarial activity against CQ-sensitive and CQ-resistant strains of Plasmodium falciparum.

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4‐amino‐7‐chloroquinolines yielded a series of new 7‐chloro‐4‐aminoquinoline‐triazine hybrids exhibiting high in vitro activity against W2 (chloroquine‐resistant) and D6 (chloroquine‐sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC‐PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine‐resistant strains (W2 clone) of P. falciparum.

Anticancer activity of 4-aminoquinoline-triazine based molecular hybrids

In this study the potential for anticancer activity of 4-aminoquinoline-triazine based hybrids has been investigated on 60 human cancer cell lines (NCI 60). The representative compounds show activity on a range of cell lines and apoptosis as the mode of growth inhibition.

Novel 3,5-bis(arylidiene)-4-piperidone based monocarbonyl analogs of curcumin: anticancer activity evaluation and mode of action study

A series of eighteen novel 3,5-bis(arylidiene)-4-piperidone based symmetrical monocarbonyl analogs of curcumin were synthesised and a subset was screened by National Cancer Institute (NCI), USA for their anticancer activity. Dose–response studies and the mechanism of action investigation suggest that most active compounds are apoptosis inducers.

C5-curcuminoid-4-aminoquinoline based molecular hybrids: design, synthesis and mechanistic investigation of anticancer activity

The privileged scaffolds of curcumin and 4-aminoquinolines are extensively used in the design and synthesis of biodynamic agents having remarkable efficacy against diseases like cancer and malaria. Therefore, we anticipated that covalent hybridization of these two pharmacophores via the triazole linker may lead to molecules with better anticancer activity. The synthesized hybrid compounds were tested for their anti-cancer activity on 60 human cancer cell lines, which represent diverse histologies. Our study has identified a set of these hybrids that showed excellent growth inhibition at nano-molar concentrations. The mechanistic investigations through a series of assays showed apoptotic induction as a cause for their displayed anticancer activity.

Highly active 4-aminoquinoline–pyrimidine based molecular hybrids as potential next generation antimalarial agents

In order to overcome the problem of emerging drug resistance in malarial chemotherapy, a series of highly active 4-aminoquinoline–pyrimidine hybrids were synthesized and evaluated for their antimalarial activity against CQ-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum in an in vitro assay. The most active hybrid 19f exhibited 74-fold better potency than chloroquine and 4-fold better potency than artesunate against the drug-resistant strain of P. falciparum. Compound 19e, when evaluated for in vivo activity in the P. berghei-mouse malaria model showed 93.9% parasite suppression at 30 mg kg−1 dose on Day 4 with a mean survival time of 11 days. To gain insights towards the mechanism of action of these hybrids, heme binding and molecular modelling studies were performed on the most active hybrids. It was observed that inhibition of formation of β-hematin and dihydrofolate reductase-thymidylate synthase Pf-DHFR-TS enzyme could be associated with the observed antimalarial activity of these compounds.

Insights into activity enhancement of 4-aminoquinoline-based hybrids using atom-based and field-based QSAR studies

Malaria has remained one of the most devastating diseases, and the problem has further complicated due to wide spread of chloroquine (CQ)-resistance strain of Plasmodium falciparum. In order to overcome this problem, efforts are being made to develop new chemical entities that can solve the problem of drug resistance. In this context, both atom-based and field-based 3D-QSAR (3-Dimensional quantitative structure–activity relationship) studies were carried out for some of our recently reported 4-aminoquinoline hybrids. The four models generated have shown good correlation coefficients r2 (0.97, 0.97, 0.94, and 0.95) and test set prediction coefficients q2 (0.86, 0.88, 0.93, and 0.89). The 3D-QSAR models gave insights into the facts about the changes in the activity pattern with the change in pyrimidine, triazine, and triazole rings. These models will be useful in the future projects of developing new antimalarial compounds against both the CQ-sensitive and CQ-resistance strains of P. falciparum.Graphical abstract