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

Abstract

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. background: Last 3 decades, globally 1.5–2 million individuals globally died each year due to invasive fungal infection (IFI).Candida albicans and Aspergillus niger have been reported as the most infectious and mortality-inducing fungal strains among all pathogenic fungi. Aim & Objective: 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. objective: To overcome this, we came up with a technique that is molecular hybridization, green chemistry, and one-pot multicomponent reaction of Pyranopyrazoles and Pyrazolopyrano-pyrimidine scaffold derivative Material and Method: 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. method: In the present work, New Chemical Entities (NCE’s) were developed on the basis of SAR. 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). Top docking molecule synthesis was carried out using green chemistry techniques and evaluated for in-vitro antifungal activity against Candida albicans and Aspergillus niger. Result 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. result: Based on the primary nucleus of known drugs, two series (B1-12 and C1-11) were developed. Both series were selected for drug-likeness, and all NCEs except standard complied with Lipinski's rule of five.9 Molecules from series-B and 8 molecules from series-C have reported higher oral absorption than standard drugs and have been screened since they are less toxic than standard.The comparative docking analysis of all three proteins acknowledge that 6 molecules from series-B and 5 molecules from series-C showed good dock score and binding interaction as that of standard and based on ADMET, dock score and interaction these are molecules selected for synthesis. In-vitro antifungal activity against Candida albicans and Aspergillus niger. Molecules B-3 and C-4 showed the highest zone of inhibition activity, while B-2 and C-2 showed the lowest zone of inhibition against Candida albicans. Conclusion: Bicyclic ring (series B) showed better activity as compare to fused tricyclic ring (series C). conclusion: Bicyclic ring (series B) showed better activity as compare to fused tricyclic ring (series C).