Naphthyl bearing 1,3,4-thiadiazoleacetamides targeting the parasitic folate pathway as anti-infectious agents: in silico , synthesis, and biological approach

• Published in: MedChemComm 2023-12, Vol.14 (12), p.2768-2781
• Main Authors: Pal, Kavita, Lala, Sahil, Agarwal, Priyanka, Patel, Tarosh S, Legac, Jenny, Rahman, Md Ataur, Ahmedi, Saiema, Shahid, Nida, Singh, Sneha, Kumari, Kajal, Madhav, Hari, Sen, Abhik, Manzoor, Nikhat, Dixit, Bharat C, Van Zyl, Robyn, Rosenthal, Philip J, Hoda, Nasimul
• Format: Article
• Language: English
• Subjects: Antileishmanial agents; Antimalarial activity; Antimalarial agents; Antiparasitic agents; Chemical synthesis; Chemistry; Dihydrofolate reductase; Drug resistance; Folic acid; Functional analysis; Hybrids; Infectious diseases; Malaria; Molecular docking; Parasite resistance; Parasites; Parasitic diseases; Physiochemistry; Promastigotes; Reductases; Software; Structural analysis; Structure-function relationships; Toxicity; Toxicity testing; Vector-borne diseases
• ISSN: 2632-8682; 2040-2503; 2632-8682; 2040-2511
• DOI: 10.1039/d3md00423f

Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)- -(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of dihydrofolate reductase ( DHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis. The synthesized compounds were evaluated for their antimalarial activity against CQ-sensitive NF54 and CQ-resistant W2 strain. Compounds T5 and T6 are the most active compounds having anti-plasmodial activity against NF54 with IC values of 0.94 and 3.46 μM respectively. Compound T8 is the most active against the W2 strain having an IC of 3.91 μM. Further, these active hybrids (T5, T6, and T8) were also evaluated for enzyme inhibition assay against DHFR. All the tested compounds were non-toxic against the Hek293 cell line with good selectivity indices. Hemolysis assay also showed non-toxicity of these compounds on normal uninfected human RBCs. molecular docking studies were carried out in the binding pocket of both the wild-type and quadruple mutant -DHFR-TS to gain further insights into probable modes of action of active compounds. ADME prediction and physiochemical properties support their drug-likeness. Additionally, they were screened for antileishmanial activity against promastigotes to explore broader applications. Thus, this study provides molecular frameworks for developing potent antimalarials and antileishmanial agents.