Kuldeep 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.

Discovery of a new class of dithiocarbamates and rhodanine scaffolds as potent antifungal agents: synthesis, biology and molecular docking

Drug resistance to established antifungals such as azole derivatives (fluconazole and ketoconazole) is driving the rise in global mortality due to fungal infection. Identification of new molecular entities structurally unrelated to these may represent a valid strategy to overcome resistance to currently available drugs. In an effort to develop highly potent antifungal agents, we report herein a series of 27 compounds of dithiocarbamate and the rhodanine molecules containing pyridine moiety and their antifungal activity. Among the synthesized compounds, several analogues have shown potent antifungal activity. The potent compounds against Candida albicans strain were further tested for in vitro anticandidal activity and amphotericin B-resistant strain of Candida albicans. Several derivatives 4a–f, 6, and 7k–n were found to be more effective (MIC = 0.39 – 3.12 μg mL−1) against Candida albicans MTCC183 and further these compounds, except 4e, 4f, and 7m, showed significant activity against amphotericin B-resistant strain of Candida albicans than that of fluconazole. Moreover, these analogues did not exhibit any toxicity up to MIC 3.12 μg mL−1 against mammalian cell line L929. A molecular docking study was undertaken to understand the mode of action of the active compounds towards prospective target lanosterol 14α-demethylase (CYP-51).

Synthesis of hybrid 4-anilinoquinoline triazines as potent antimalarial agents, their in silico modeling and bioevaluation as Plasmodium falciparumtransketolase and β-hematin inhibitors

Analogues of a novel class of hybrid 4-anilinoquinoline triazines have been synthesized with the aim of identifying the compounds with improved antimalarial activity preserving the potency of parent drug chloroquine (CQ). All the synthesized molecules were evaluated in vitro for their antimalarial activity against chloroquine-sensitive 3D7 and chloroquine-resistant K1 strains of P. falciparum. Molecules were also screened for their cytotoxicity towards VERO cell line. Sixteen compounds (17, 19, 26, 27, 29, 31, 32, 33, 35, 36, 37, 39, 40, 49, 50, and 52) exhibited excellent antimalarial activity with IC50 values ranging from 1.36–4.63 ng ml−1 and were also found to be nontoxic with good selectivity index. In silico activity prediction as well as enzyme inhibitory activity against P. falciparumtransketolase reveals that the molecules are also good inhibitors of the enzymeP. falciparumtransketolase. The compound 52 showed good in vivo activity by oral route and resulted in survival of 3 out of 5 mice till day 28.

Synthesis and biological evaluation of a new class of 4-aminoquinoline-rhodanine hybrid as potent anti-infective agents.

Synthesis of novel 4-aminoquinoline-rhodanine hybrid using inexpensive starting materials via easy to operate methodology, and their biological activity is reported. All the compounds were screened for their in vitro antimalarial activity against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum, and their cytotoxicity toward VERO cell line. Compounds 9, 19, 21 and 23 exhibited excellent antimalarial activity with IC50 value ranging from 13.2 to 45.5 nM against chloroquine-resistant (K1) strain. Biochemical studies revealed that inhibition of hemozoin formation is the primary mechanism of action of these analogs for their antimalarial activity. Additionally, some derivatives (14, 18 and 26) of this series also exhibited the antimycobacterial activity against H37Rv strain of Mycobacterium tuberculosis with MIC value of 6.25 μM.

Discovery of triazine mimetics as potent antileishmanial agents.

The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents. Most of the synthesized derivatives exhibited better activity against intracellular amastigotes (IC50 ranging from 0.77 to 10.32 μM) than the control, pentamidine (IC50 = 13.68 μM), and are not toxic to Vero cells. Compounds 14 and 15 showed significant in vivo inhibition of 74.41% and 62.64%, respectively, in L. donovani/hamster model. Moreover, expansion of Th1-type and suppression of Th2-type immune responses proved that compound 14 stimulates mouse macrophages to prevent the progression of leishmania parasite. The molecular docking studies involving PTR1 protein PDB further validated the concepts involved in the design of these compounds. Among the investigated analogues, compound 14 has emerged as the potential one to enlarge the scope of the study.

Synthesis and antibacterial evaluation of novel 8-fluoro Norfloxacin derivatives as potential probes for methicillin and vancomycin-resistant Staphylococcus aureus

A series of novel 8-fluoro Norfloxacin derivatives and the hybrids of its piperazinyl derivatives incorporated with 1,3,5-triazine and pyrimidine were synthesized. All the above compounds were evaluated for their antibacterial activity against Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus and methicillin & vancomycin-resistant S. aureus. Among all, compounds having Morpholine, N-methyl/phenyl/benzyl/pyrimidinyl piperazines and n-butylamine substitution at C-7 position, have shown increased potency in comparison to norfloxacin and ciprofloxacin.

Design and synthesis of a new class of 4-aminoquinolinyl- and 9-anilinoacridinyl Schiff base hydrazones as potent antimalarial agents.

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.

New class of methyl tetrazole based hybrid of (Z)-5-benzylidene-2-(piperazin-1-yl)thiazol-4(%H)-one as potent antitubercular agents

In search of potential therapeutics for tuberculosis, we describe here the synthesis and in vitro antitubercular activity of a novel series of thiazolone piperazine tetrazole derivatives. Among all the synthesized derivatives, four compounds (10, 14, 20 and 33) exhibited more potent activity (MIC=3.08, 3.01, 2.62 and 2.51 μM) than ethambutol (MIC=9.78 μM) and pyrazinamide (MIC=101.53 μM) against Mycobacterium tuberculosis. Furthermore, they displayed no toxicity against Vero cells (C1008) and mouse bone marrow derived macrophages (MBMDMϕ). These investigated analogues have emerged as possible lead molecule to enlarge the scope of the study.