Abstract: Background and Objective: Factor Xa is an essential enzyme in the blood coagulation cascade. Inhibition of factor Xa can overcome confines of the current antithrombotic therapy. Here, the aim of this report a series of novel non-basic compounds possessing sulfide, sulfoxide and sulfone groups as S4 binding elements and sulfonamide, sulfide and sulfone bearing aryl groups as S1 binding moieties and their human factor Xa (FXa or hFXa) inhibitory activity. Materials and Methods: Measurement of direct Fxa was done using a chromogenic substrate hydrolysis assay using a micro plate reader (Flex Station III, Molecular Devices). Initial screening was done using two concentrations of the compounds (500 and 100 μM). The IC50 values were determined for those compounds that caused>50% reproducible inhibition of coagulation enzyme in the initial screening at 100 μM concentration. Clotting time was measured using a BBL Fibro system fibrometer (Becton-Dickinson, Sparles, MD) in a standard one-stage re-calcification assay. Docking studies were performed using Glide tool of Schrödinger 2009. Results: Among the 20 compounds so evaluated, three compounds exhibited moderate inhibition of hFXa, while two of the compounds (34 and 35c) exhibited good hFXa inhibition with IC50 values of 29.2 and 16.1μM with an efficacy of 70 and 75%, respectively. Conclusion: A series of ‘V’ shaped molecules were designed, synthesized and evaluated for their FXa inhibitory activity. Out of the 20 compounds screened for activity, two compounds (34 and 35c) showed activity in low micromolar range. The SAR studies indicated the presence of sulfide or sulfoxide P4 as an essential feature for FXa inhibitory activity. Sulfonamide as a linker between the P1 ligand and the main scaffold offered more potent compounds. Docking studies indicated strong interaction of the compound 35c within the active site. The compounds have advantage of possessing neutral/acidic functionalities unlike the existing FXa inhibitors having basic character which hampers their oral bioavailability.