Green Chemistry and In silico Techniques for Synthesis of Novel Pyranopyrazole and Pyrazolo-pyrano-pyrimidine Derivatives as Promising Antifungal Agents.

BACKGROUND: Every year Invasive Fungal Infections (IFI) are globally affecting millions of people. Candida albicans and Aspergillus niger have been reported as the most infectious and mortality-inducing fungal strains among all pathogenic fungi. AIMS & OBJECTIVES: To tackle this problem in the current study Pyranopyrazoles and Pyrazolopyrano- pyrimidine derivatives were developed using molecular hybridization, green chemistry and one-pot multicomponent reaction. MATERIALS AND METHODS: In the present work, New Chemical entities (NCE's) were developed on the basis of Structure activity relationship. All designed NCE's were screened for ADMET studies using the QikProp module of Schrodinger software. NCE's with zero violations were further docked on the crystal structure of 14α demethylase, cytochrome P450 and thymidine synthase (PDB ID: 5V5Z, 7SHI, 1BID). Selected molecules were synthesized using green chemistry techniques and evaluated for in vitro antifungal activity against Candida albicans and Aspergillus niger. RESULTS AND DISCUSSION: Designed NCE's (B1-12 and C1-11) showed favorable results in ADMET studies. In the docking study six compounds from series-B and five molecules from series- C showed good dock score and binding interaction when compared with the standard drugs. Compounds B-3 and C-4 showed the highest zone of inhibition activity against Candida albicans, where as B-1 and C-3 had shown highest zone of inhibition activity against Aspergillus niger. CONCLUSION: Bicyclic ring (series B) showed better activity as compare to fused tricyclic ring (series C).

Comparative Docking Studies: A Drug Design Tool for Some Pyrazine- Thiazolidinone Based Derivatives for Anti-HIV Activity.

BACKGROUND: Acquired immunodeficiency Syndrome (AIDS) is caused by Human immunodeficiency virus type 1 (HIV-1). Pyrazine and Thiazolidinone pharmacophore has diverse biological activities including anti HIV activity. AIMS AND OBJECTIVES: To study binding behavior of Pyrazine- thiazolidinone derivatives on four different crystal structures of HIV- 1RT.These molecules which were already reported as anti-TB were investigated for dual activity as Anti-HIV and Anti-TB. MATERIALS AND METHODS: In the present study we describe a comparative docking study of twentythree derivatives of N-(4-oxo-2 substituted thiazolidin-3-yl) pyrazine-2-carbohydrazide. Binding pattern of these derivatives was gauged by molecular docking studies on four different receptors bearing PDB code 1ZD1, 1RT2, 1FKP and 1FK9 of HIV-RT enzyme using V. Life MDS software Genetic algorithm docking method. RESULT AND DISCUSSION: The studies revealed hydrogen bonds, hydrophobic interaction and pi-pi interactions playing significant role in binding of the molecules to the enzyme. CONCLUSION: Most of the molecules have shown good dock score and binding energy with anti-HIV receptors but Molecules 13 and 14 have potential to act as anti-tubercular and Anti HIV and hence can be further explored for dual activity.

Exploring Pyrimidine Pharmacophore as Thymidine Monophosphate Kinase Inhibitors for Antitubercular Activity: A Review.

Tuberculosis (TB) has been declared as a health emergency due to emergence of resistant strains of M. tuberculosis, multidrug resistant (MDR), extensively drug resistant (XDR) TB strains and totally drug resistant tuberculosis (TDR-TB) reported recently in some parts of the world. Therefore, the current situation necessitates developing new antitubercular agents acting on novel targets for effectively controlling TB. Thymidine Monophosphate Kinase (TMPKmt) enzyme is one such target, which is being explored. This review focuses on Structure Activity Relationship studies (SARs) and computational studies of various nucleotide and nucleoside derivatives of pyrimidine analogs reported as TMPKmt inhibitors.