Raghu Raj

Azide-alkyne cycloaddition en route to 1H-1,2,3-triazole-tethered 7-chloroquinoline-isatin chimeras: Synthesis and antimalarial evaluation

We describe the synthesis and antimalarial activities of 1H-1,2,3-triazole tethered 7-chloroquinoline-isatin hybrids. Activity against cultured parasites was dependent on the C-5 substituent of the isatin ring as well as the alkyl chain length between the isatin and 7-chloroquinoline moieties. Compound 8h, with an optimum alkyl chain length (n = 3) and a chloro substituent at the C-5 position of the isatin ring, displayed the best activity among the test compounds, with IC50 value of 1.21 μM against cultured W2-strain Plasmodium falciparum.

Antiplasmodial and cytotoxicity evaluation of 3-functionalized 2-azetidinone derivatives

3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-β-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered β-lactam exhibiting IC(50) values of 1.13, 1.21 and 1.00 μM against 3D7, K1 and W2 strains respectively.

7‐Chloroquinoline–isatin Conjugates: Antimalarial, Antitubercular, and Cytotoxic Evaluation

A series of twenty piperazine‐tethered 7‐chloroquinoline–isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl‐mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine‐resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC50 of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.

Urea/oxalamide tethered β-lactam-7-chloroquinoline conjugates: synthesis and in vitro antimalarial evaluation.

The manuscript pertains to the synthesis of urea/oxalamide tethered β-lactam-7-chloroquinoline conjugates with well modulated chain lengths and their antimalarial evaluation. The results reveal the dependence of activity profiles on the N-1 substituent of the β-lactam ring, the nature of the linker as well as the length of the alkyl chain. The most potent of the tested compounds showed an IC50 of 34.97 nM against chloroquine resistant W2 strain of Plasmodium falciparum.

4‐Aminoquinoline‐β‐Lactam Conjugates: Synthesis, Antimalarial, and Antitubercular Evaluation

A library of quinoline‐β‐lactam‐based hybrids was synthesized and tested for their antimalarial and antitubercular activities. The present antimalarial data showed the dependence of activity on the nature of linker, N‐1 substituent of the β‐lactam ring as well as the length of alkyl chain. Most of the compounds are not as efficient as chloroquine in inhibiting the culture growth of Plasmodium falciparum W2 strain. Nevertheless, the synthesized hybrids showed better antitubercular activities (up to five times) compared with cephalexin (up to three times) and ethionamide.

Recent advances (2015–2016) in anticancer hybrids

In spite of the development of a large number of novel anticancer drugs over the years, Cancer remains as a prominent cause of death, worldwide. Numerous drugs that are currently in clinical practice have developed multidrug resistance along with fatal side effects. Therefore, the utilization of single-target therapy is incapable of providing an effective control on the malignant process. Molecular hybridization, involving a combination of two or more pharmacophores of bioactive scaffolds to generate a single molecular architecture with improved affinity and activity, in comparison to their parent molecules, has emerged as a promising strategy in recent drug discovery research. Hybrid anticancer drugs are of great therapeutic interests since they can potentially overcome most of the pharmacokinetic drawbacks encountered with conventional anticancer drugs. Strategically, the design of anticancer drugs involved the blending or linking of an anticancer drug with another anticancer drug or a carrier molecule which can efficiently target cancer cells with improved biological potential. Major advantages of hybrid anticancer drugs involved increased specificity, better patient compliance, and lower side effects along with reduction in chemo-resistance. The successful utilization of this technique in design and synthesis of novel anticancer hybrids has been well illustrated and documented in the literature. The purpose of the present review article will be to provide an emphasis on the recent developments (2015-16) in anticancer hybrids with insights into their structure-activity relationship (SAR) and mechanism of action.

1H-1,2,3-Triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates: synthesis and antimalarial evaluation.

A series of 1H-1,2,3-triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates have been synthesized and evaluated for their antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum. The most potent of the test compound with an optimum combination of 3-hydroxy-indole ring and a n-butyl linker displayed an IC50 value of 69 nM.

Discovery of highly selective 7-chloroquinoline-thiohydantoins with potent antimalarial activity

A series of C-3 thiourea functionalized β-lactams, β-lactam-7-chloroquinoline conjugates and 7-chloroquinoline-thiohydantoin derivatives were prepared with the aim of probing antimalarial structure-activity relationships. 7-Chlorquinoline-thiohydantoin derivatives were found to be potent inhibitors of cultured Plasmodium falciparum, with the most potent and non-cytotoxic compound exhibiting an IC50 of 39.8 nM. Studies of β-hematin formation suggested that inhibition of haemozoin formation could be primary mechanism of action, with IC50 values comparable to those of chloroquine. Evaluation of cytotoxicity against HeLa cells demonstrated high selective indices.

4-Aminoquinoline-hybridization en route towards the development of rationally designed antimalarial agents

The resistance of Plasmodium falciparum, the causative agent of malaria, against quinine and chloroquine along with the lack of malaria vaccines has encouraged the development of various synthetic strategies towards biologically active scaffolds. An emerging strategy in medicinal chemistry, termed molecular hybridization, involves the covalent fusion of two or more drugs, active compounds, and/or pharmacophoric units into a hybrid compound, with fascinating activities and multiple but not essentially simultaneous pharmacological targets. 4-Aminoquinolines are considered as promising antimalarials and 4-aminoquinoline hybridization is considered as an attractive and feasible approach for the development of new molecular frameworks for averting and delaying the emergence of drug resistance along with improved efficacy. The present review article describes the recent developments on the 4-aminoquinoline-hybridization towards the development of new antimalarials.