QSAR analysis of some 5-amino-2-mercapto-1,3,4-thiadiazole based inhibitors of matrix metalloproteinases and bacterial collagenase Ashutosh Jamloki, a,  C. Karthikeyan, a,  N. S. Hari Narayana Moorthy b and P. Trivedi a, * a Department of Pharmacy, SGSITS, Indore, India b School of Pharmaceutical Sciences, RGPV, Bhopal, India Received 27 October 2005; revised 19 March 2006; accepted 7 April 2006 Available online 8 May 2006 Abstract—A quantitative structure–activity relationship (QSAR) study has been performed on 5-amino-2-mercapto-1,3,4-thiadia- zole based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase known as Clostridium histolyticum collage- nase (ChC) to understand the structural features influencing the affinity of these inhibitors towards the enzyme. The compounds in the selected series were characterized by topological and fragmental descriptors calculated using QuaSAR module of molecular operating environment (MOE). An indicator variable was also assigned to account for the presence of amide function in vicinity of sulfonamide group in the parent structure. Correlations between different inhibitory activities and calculated predictor variables were established through stepwise multiple regression employing the method of least squares. The results of the study indicates that MMP inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadiazoles can be successfully explained in terms of topology of the mole- cule. The obtained correlations also suggest that increase in the number of fluorine atoms in the aromatic ring will augment inhib- itory activity of these molecules against all the MMPs probably by virtue of hydrogen bond interaction with some complementary groups in the active site of the enzymes. One prime requirement for better inhibition of MMPs (except for MMP-1) and ChC iden- tified from the present study is the presence of amide function in vicinity of sulfonamide group in the parent structure as suggested by the presence of indicator variable in almost all correlations. While MMP-1 and ChC inhibitory activity of the compounds studied is shown to be dependent on Kier’s first order carbon valence molecular connectivity index indicating that increase in branching and presence of heteroatoms in the molecule will improve the MMP-1 and ChC inhibitory potency of 5-amino-2-mercapto-1,3,4-thia- diazoles, correlations derived for other enzymes (MMP-2, MMP-8, MMP-9) are quite similar. In addition to the number of fluorine atoms and presence of indicator variable, MMP-2, MMP-8 and MMP-9 inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadia- zoles is found to be dependent on Kier’s alpha modified index of third order in such a way that infer, terminally branched functions will increase the affinity of these molecules to the MMPs. Ó 2006 Elsevier Ltd. All rights reserved. MMPs also called Matrixins are a family of structurally related zinc containing endopeptidases capable of cleav- ing several macromolecules of the extracellular matrix such as collagens, elastin, fibronectin, laminin, and aggrecan. 1,2 The mammalian MMP family is now known to include at least 23 enzymes. Based on their structure and substrate specificity, the human MMPs are roughly divided into five groups: collagenases, gela- tinases, stromelysins, membrane-type (MT) metallopro- teinases, and the others, and it is likely that other members will be discovered in the next few years. 3 These MMPs have been implicated in the tissue remodeling at various stages of human development, wound healing, and disease. Their activation and upregulation results into tissue degradation leading to a variety of diseases, some of which are cancer, 4–7 rheumatoid arthritis, 8,9 multiple sclerosis, 10,11 and congestive heart failure. 12,13 In view of such wide-ranging clinical relevance, it is no wonder that the search for clinically useful inhibitors of these enzymes has been in the focus of intensive research. Several MMP inhibitors have reached up to clinical trials and a vast majority of them are hydroxa- mic acid derivatives, such as batimastat (BB-94), marim- astat (BB-2516), trocade (Ro 32-3555), and BAY 12-9566 (Fig. 1). 14–22 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.04.014 Keywords: QSAR; MMP; MOE. * Corresponding author. Tel./fax: +91 731 2368582; e-mail: prof_piyushtrivedi@yahoo.com   These two authors contributed equally to this work. Bioorganic & Medicinal Chemistry Letters 16 (2006) 3847–3854